Method for Producing 4-Oxoquinoline Compound

ABSTRACT

The present invention provides a compound useful as a synthetic intermediate for an anti-HIV agent having an integrase inhibitory activity, and a production method thereof, and a production method of an anti-HIV agent using the synthetic intermediate. Specifically, for example, a compound represented by the formula (2′): 
     
       
         
         
             
             
         
       
     
     wherein R is a fluorine atom or a methoxy group, and R 400  is a hydrogen atom or a C 1 -C 4  alkyl group, or a salt thereof, and a production method thereof, and a production method of an anti-HIV agent using the synthetic intermediate.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a compound useful as a syntheticintermediate for an anti-HIV agent having an integrase inhibitoryactivity and a production method thereof. Moreover, the presentinvention relates to a production method of an anti-HIV agent, whichuses the synthetic intermediate, and the like.

BACKGROUND OF THE INVENTION

Patent reference 1 discloses a production method of a 4-oxoquinolinecompound represented by the formula [III]:

wherein each symbol is as described in the patent reference 1(hereinafter sometimes to be abbreviated as compound [III]), andspecifically, the following production methods are known.

Production Method 1-1 (See Patent Reference 1: Page 67)

Each symbol in the scheme is as described in the patent reference 1.

This production method is also described in patent reference 2, page 64(each symbol in the scheme is also described in patent reference 2).

Production Method 1-2 Example of Production Method Using Compound [9]Having a Hydroxyl-Protecting Group (See Patent Reference 1: Page 71)

Each symbol in the scheme is as described in patent reference 1.

This production method is also described in patent reference 2, page 68(each symbol in the scheme is also described in patent reference 2).

Production Method 2-1 (See Patent Reference 1: Page 72)

Each symbol in the scheme is as described in patent reference 1.

This production method is also described in patent reference 2, page 69(each symbol in the scheme is also described in patent reference 2).

Production Method 2-2 Example of Production Method IncludingIntroduction-Removal Step of Hydroxyl-Protecting Group (See PatentReference 1: Page 74)

Each symbol in the scheme is as described in patent reference 1.

This production method is also described in patent reference 2, page 72(each symbol in the scheme is also described in patent reference 2).

Production Method 3 (See Patent Reference 1: Page 76)

Each symbol in the scheme is as described in patent reference 1.

This production method is also described in patent reference 2, page 74(each symbol in the scheme is also described in patent reference 2).

Production Method 4 (See Patent Reference 1: Page 77)

Examples of production methods of the above-mentioned compound [12] aremore concretely given below.

Each symbol in the scheme is as described in patent reference 1.

Production Method 5 (See Patent Reference 1: Page 79)

Each symbol in the scheme is as described in patent reference 1.

The production method is also described in patent reference 2, page 78(each symbol in the scheme is also described in patent reference 2).

The above-mentioned production method 1-1 and production method 2-1respectively relate to a production method of compound [1-2] andcompound [1-5] corresponding to the above-mentioned compound [III].

The production method 1-2, production method 2-2 and production method 5show production examples including introduction-removal ofhydroxyl-protecting group.

In addition, production method 3 discloses a method for introducing asubstituent after formation of a 4-oxoquinoline ring, and productionmethod 4 describes examples of production method of compound [12] morespecifically.

Moreover, patent reference 1 discloses, as one of the compoundsparticularly useful as anti-HIV agents from among compounds [III],6-(3-chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid (hereinafter sometimes to be abbreviated as compound (10)) and aproduction method thereof.

Specifically, Example 4-32 in patent reference 1 describes the followingproduction example.

In addition, production of 2,4-difluoro-5-iodobenzoic acid (startingmaterial) is disclosed in patent reference 1, Example 4-33, step 1.

wherein NIS is N-iodosuccinimide, Catalyst is a catalyst, and the othersymbols are as defined in patent reference 1.

This production method is also described in patent reference 2, page112, Reference Example 9.

As a production method similar to this production method, patentreference 3 describes, at page 23, Example 2-1, a production methodwherein the hydroxyl-protecting group is a tert-butyldimethylsilylgroup. Further, patent reference 3, page 12, Reference Example 1; page17, Example 1 and page 39, Example 2-4 describe a method of directlyproducing compound (10) from a compound wherein a hydroxyl-protectinggroup is tert-butyldimethylsilyl group, as shown below.

Moreover, patent reference 1, page 81, Reference Example 1, or patentreference 2, page 80, Reference Example 1 disclose that2,3-dichlorobenzylzinc chloride which is an analog of3-chloro-2-fluorobenzylzinc bromide produced in the above-mentioned step6, can be produced in the same manner from 2,3-dichlorobenzyl chloride.

Patent reference 3 discloses a production method of compound (10).

Specifically, patent reference 3 describes the following productionexample in Example 2-2, page 28.

wherein DBU is 1,8-diazabicyclo[5.4.0]undecene, Catalyst is a catalyst,and the other symbols are as defined in patent reference 3.

While patent reference 1, patent reference 2 and patent reference 3disclose production methods of compound (10), the production methodsembrace the following aspects.

-   -   In the final step (alkoxylation, particularly methoxylation), a        dimer is by-produced depending on the base to be used. In this        event, a removal step of the by-produced dimer is further        necessary, which decreases the yield greatly.    -   When sodium fluoride by-produced in the final step        (alkoxylation, particularly methoxylation) is acidified in the        treatment step, hydrofluoric acid is produced and corrodes the        production facility. Thus, a removal operation of sodium        fluoride is essential and the operation is complicated.    -   There is a concern about an unfavorable influence of        hydrofluoric acid produced in the ring-closing step on the        production facility, and therefore, the method is not of a level        satisfactory as an industrial production method.    -   Removal of the product by-produced in a reaction to insert        compound [IIb] is complicated (since alkylzinc derivative is        used together with a palladium catalyst, an operation to remove        zinc salt and palladium salt as impurities is necessary and the        operation is complicated).    -   Plural operations are necessary to protect hydroxyl group with        methyl chloroformate in a preliminary step of the reaction to        insert compound [IIb], and to deprotect the group in a later        step, and the operation is complicated    -   A step using 3-chloro-2-fluorobenzyl bromide for the production        of compound [IIb] is not beneficial for industrial production,        since the compound shows high tearing property.

The above-mentioned production method including these steps isassociated with many aspects to be improved for industrial production,and the development of a more superior production method of compound(10) is desired.

In addition, while non-patent reference 1 describes the followingbenzoic acid compound and the like, it provides no description of thecompound (2′) of the present invention to be explained in detail in thefollowing.

Moreover, patent reference 4 describes, in the ring-closing reaction forforming a 4-oxoquinoline skeleton, a production example of a4-oxoquinoline skeleton from the following acrylic acid ester and thelike. However, it provides no description of the production method ofcompound (9) from compound (7), or compound (8) from compound (6-B) ofthe present invention to be explained in detail in the following.

Patent reference 5 (see page 11, compound 2-12) describes the followingbenzoic acid compound [A] and the like as photosensitive materials.However, it provides no description of the compound (2′) of the presentinvention to be explained in detail in the following.

Moreover, non-patent reference 2 describes the following benzoic acidcompound [B] and the like (see scheme 2). However, it provides nodescription of the compound (2′) of the present invention to beexplained in detail in the following.

In addition, non-patent reference 3 describes the following benzoic acidcompounds [C] and [D] and the like (see page 3512, compounds 10 and 12).However, it provides no description of the compound (2′) of the presentinvention to be explained in detail in the following.

-   [Patent reference 1)] WO 04/046115-   [Patent reference 2] WO 05/113509-   [Patent reference 3] WO 05/113508-   [Patent reference 4] U.S. Pat. No. 4,695,646 (column 15, line 40)-   [Patent reference 5] JP-A-11-84556-   [Non-patent reference 1] Zhurnal Organicheskoi Khimii, vol. 6,    number 1, pages 68-71, 1970 (page 70, 3)-   [Non-patent reference 2] Synlett, vol. 5, p. 447-448, 1996-   [Non-patent reference 3] Macromolecules, vol. 28, p. 3509-3515, 1995

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide a compound useful as asynthetic intermediate for an anti-HIV agent having an integraseinhibitory activity and a production method thereof, and a productionmethod of an anti-HIV agent using the synthetic intermediate.

Means of Solving the Problems

In view of the above-mentioned object, the present inventors haveconducted intensive studies in an attempt to find an improved productionmethod of the above-mentioned compound [III], particularly compound(10), and found that a compound represented by the formula (2′)(hereinafter sometimes to be abbreviated as compound (2′)) or a saltthereof is useful as a synthetic intermediate therefor, which resultedin the completion of the present invention.

The formula (2′):

wherein R is a fluorine atom or a methoxy group, and R⁴⁰⁰ is a hydrogenatom or a C₁-C₄ alkyl group.

More specifically, the present invention is as shown in the following[1]-[45].

[1] A compound represented by the formula (2′):

wherein R is a fluorine atom or a methoxy group, and R⁴⁰⁰ is a hydrogenatom or a C₁-C₄ alkyl group (hereinafter sometimes to be abbreviated ascompound (2′)), or a salt thereof.[2] The compound of the above-mentioned [1], wherein R is a methoxygroup, or a salt thereof.[3] Use of a compound represented by the formula (8-1):

wherein X¹⁰⁰ is a halogen atom (hereinafter sometimes to be abbreviatedas compound (8-1)) for the production of a compound represented by theformula (2′):

wherein R is a fluorine atom or a methoxy group, and R⁴⁰⁰ is a hydrogenatom or a C₁-C₄ alkyl group,or a salt thereof.[4] Use of a compound represented by the formula (8-1):

wherein X¹⁰⁰ is a halogen atom, anda compound represented by the formula (2-1):

wherein R is a fluorine atom or a methoxy group, R³⁰⁰ is a C₁-C₄ alkylgroup, and X²⁰⁰ is a halogen atom (hereinafter sometimes to beabbreviated as compound (2-1)) in the presence of a metal atom M¹, forthe production of a compound represented by the formula (2′):

wherein R is a fluorine atom or a methoxy group, and R⁴⁰⁰ is a hydrogenatom or a C₁-C₄ alkyl group,or a salt thereof.[5] Use of a compound represented by the formula (2′):

wherein R is a fluorine atom or a methoxy group, and R⁴⁰⁰ is a hydrogenatom or a C₁-C₄ alkyl group,or a salt thereof, for the production of compound (10):

or a salt thereof.[6] Use of a compound represented by the formula (8-1):

wherein X¹⁰⁰ is a halogen atom, a compound represented by the formula(2-1):

wherein R is a fluorine atom or a methoxy group, R³⁰⁰ is a C₁-C₄ alkylgroup, and X²⁰⁰ is a halogen atom, and a compound represented by theformula (2′):

wherein R is a fluorine atom or a methoxy group, and R⁴⁰⁰ is a hydrogenatom or a C₁-C₄ alkyl group, or a salt thereof, for the production ofcompound (10):

or a salt thereof.[7] Use of a compound represented by the formula (2-2):

wherein R is a fluorine atom or a methoxy group, and R³⁰⁰ is a C₁-C₄alkyl group (hereinafter sometimes to be abbreviated as compound (2-2)),a compound represented by the formula (2-3):

wherein R is a fluorine atom or a methoxy group (hereinafter sometimesto be abbreviated as compound (2-3)), or a salt thereof, a compoundrepresented by the formula (3):

wherein R is a fluorine atom or a methoxy group (hereinafter sometimesto be abbreviated as compound (3)), a compound represented bythe formula (4):

wherein R is a fluorine atom or a methoxy group, and R¹⁰⁰ is a C₁-C₄alkyl group (hereinafter sometimes to be abbreviated as compound (4)),or a salt thereof, a compound represented by the formula (5):

wherein R is a fluorine atom or a methoxy group, and R¹⁰⁰ is a C₁-C₄alkyl group (hereinafter sometimes to be abbreviated as compound (5)),and a compound represented by the formula (6):

wherein R is a fluorine atom or a methoxy group, and R¹⁰⁰ is a C₁-C₄alkyl group (hereinafter sometimes to be abbreviated as compound (6)),for the production of compound (10):

or a salt thereof.[8] Use of a compound represented by the formula (2-2-A):

wherein R³⁰⁰ is a C₁-C₄ alkyl group (hereinafter sometimes to beabbreviated as compound (2-2-A)), compound (2-3-A):

or a salt thereof, compound (3-A):

a compound represented by the formula (4-A):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group (hereinafter sometimes to beabbreviated as compound (4-A)), or a salt thereof, a compoundrepresented by the formula (5-A):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group (hereinafter sometimes to beabbreviated as compound (5-A)), a compound represented by the formula(6-A):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group (hereinafter sometimes to beabbreviated as compound (6-A)), a compound represented by the formula(7):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, and R²⁰⁰ is a hydroxyl-protectinggroup (hereinafter sometimes to be abbreviated as compound (7)), and acompound represented by the formula (9):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, and R²⁰⁰ is a hydroxyl-protectinggroup (hereinafter sometimes to be abbreviated as compound (9)), for theproduction of compound (10):

or a salt thereof.[9] Use of a compound represented by the formula (2-2-B):

wherein R³⁰⁰ is a C₁-C₄ alkyl group (hereinafter sometimes to beabbreviated as compound (2-2-B)), compound (2-3-B):

or a salt thereof, compound (3-B):

a compound represented by the formula (4-B):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group (hereinafter sometimes to beabbreviated as compound (4-B)), or a salt thereof, a compoundrepresented by the formula (5-B):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group (hereinafter sometimes to beabbreviated as compound (5-B)), a compound represented by the formula(6-B):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group (hereinafter sometimes to beabbreviated as compound (6-B)), and a compound represented by theformula (8):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group (hereinafter sometimes to beabbreviated as compound (8)), for the production of compound (10):

or a salt thereof.[10] Use of a compound represented by the formula (1):

wherein R is a fluorine atom or a methoxy group (hereinafter sometimesto be abbreviated as compound (1)), or a salt thereof, a compoundrepresented by the formula (2):

wherein R is a fluorine atom or a methoxy group, and X²⁰⁰ is a halogenatom (hereinafter sometimes to be abbreviated as compound (2)), or asalt thereof, a compound represented by the formula (2-1):

wherein R is a fluorine atom or a methoxy group, R³⁰⁰ is a C₁-C₄ alkylgroup, and X²⁰⁰ is a halogen atom, a compound represented by the formula(2-2):

wherein R is a fluorine atom or a methoxy group, and R³⁰⁰ is a C₁-C₄alkyl group, a compound represented by the formula (2-3):

wherein R is a fluorine atom or a methoxy group, or a salt thereof, acompound represented by the formula (3):

wherein R is a fluorine atom or a methoxy group, a compound representedbythe formula (4):

wherein R is a fluorine atom or a methoxy group, and R¹⁰⁰ is a C₁-C₄alkyl group, or a salt thereof, a compound represented by the formula(5):

wherein R is a fluorine atom or a methoxy group, and R¹⁰⁰ is a C₁-C₄alkyl group, and a compound represented by the formula (6):

wherein R is a fluorine atom and a methoxy group, and R¹⁰⁰ is a C₁-C₄alkyl group, for the production of compound (10):

or a salt thereof.[11] Use of compound (1-A):

or a salt thereof, a compound represented by the formula (2-A):

wherein X²⁰⁰ is a halogen atom (hereinafter sometimes to be abbreviatedas compound (2-A)), or a salt thereof, a compound represented by theformula (2-1-A):

wherein R³⁰⁰ is a C₁-C₄ alkyl group, and X²⁰⁰ is a halogen atom(hereinafter sometimes to be abbreviated as compound (2-1-A)), acompound represented by the formula (2-2-A):

wherein R³⁰⁰ is a C₁-C₄ alkyl group, compound (2-3-A):

or a salt thereof, compound (3-A):

a compound represented by the formula (4-A):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, or a salt thereof, a compoundrepresented by the formula (5-A):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, a compound represented by theformula (6-A):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, a compound represented by theformula (7):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, and R²⁰⁰ is a hydroxyl-protectinggroup, and a compound represented by the formula (9):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, and R²⁰⁰ is a hydroxyl-protectinggroup, for the production of compound (10):

or a salt thereof.[12] Use of compound (1-B):

or a salt thereof, a compound represented by the formula (2-B):

wherein X²⁰⁰ is a halogen atom (hereinafter sometimes to be abbreviatedas compound (2-B)), or a salt thereof, a compound represented by theformula (2-1-B):

wherein R³⁰⁰ is a C₁-C₄ alkyl group, and X²⁰⁰ is a halogen atom(hereinafter sometimes to be abbreviated as compound (2-1-B)), acompound represented by the formula (2-2-B):

wherein R³⁰⁰ is a C₁-C₄ alkyl group, compound (2-3-B):

or a salt thereof, compound (3-B):

a compound represented by the formula (4-B):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, or a salt thereof, a compoundrepresented by the formula (5-B):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, a compound represented by theformula (6-B):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, and a compound represented by theformula (8):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, for the production of compound(10):

or a salt thereof.[13] A method of producing a compound represented by the formula (2′):

wherein R is a fluorine atom or a methoxy group, and R⁴⁰⁰ is a hydrogenatom or a C₁-C₄ alkyl group,or a salt thereof, which comprises reacting a compound represented bythe formula (8-1):

wherein X¹⁰⁰ is a halogen atom, with a compound represented by theformula (2-1):

wherein R is a fluorine atom or a methoxy group, R³⁰⁰ is a C₁-C₄ alkylgroup, and X²⁰⁰ is a halogen atom, in the presence of a metal atom M¹.[14] A method of producing the following compound (10), or a saltthereof, comprising producing compound (10):

or a salt thereof from a compound represented by the formula (2′):

wherein R is a fluorine atom or a methoxy group, and R⁴⁰⁰ is a hydrogenatom or a C₁-C₄ alkyl group, or a salt thereof.[15] A method of producing compound (10):

or a salt thereof, which comprisesa step of producing compound (2-3-A):

or a salt thereof, from a compound represented by the formula (2-2-A):

wherein R³⁰⁰ is a C₁-C₄ alkyl group;a step of producing compound (3-A):

from the above-mentioned compound (2-3-A) or a salt thereof; a step ofproducing a compound represented by the formula (4-A):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, or a salt thereof, from theabove-mentioned compound (3-A);a step of producing a compound represented by the formula (5-A):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, from the above-mentioned compound(4-A) or a salt thereof;a step of producing a compound represented by the formula (6-A):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, from the above-mentioned compound(5-A);a step of producing a compound represented by the formula (7):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, and R²⁰⁰ is a hydroxyl-protectinggroup, from the above-mentioned compound (6-A); a step of producing acompound represented by the formula (9):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, and R²⁰⁰ is a hydroxyl-protectinggroup, from the above-mentioned compound (7); anda step of producing the above-mentioned compound (10) or a salt thereoffrom the above-mentioned compound (9).[16] The production method of the above-mentioned [15], which furthercomprisesa step of producing a compound represented by the formula (2-A):

wherein X²⁰⁰ is a halogen atom, or a salt thereof, from compound (1-A):

or a salt thereof;a step of producing a compound represented by the formula (2-1-A):

wherein R³⁰⁰ is a C₁-C₄ alkyl group, and X²⁰⁰ is a halogen atom, fromthe above-mentioned compound (2-A) or a salt thereof; anda step of producing a compound represented by the formula (2-2-A):

wherein R³⁰⁰ is a C₁-C₄ alkyl group, from the above-mentioned compound(2-1-A).[17] A method of producing compound (10):

or a salt thereof, which comprisesa step of producing compound (2-3-B):

or a salt thereof, from a compound represented by the formula (2-2-B):

wherein R³⁰⁰ is a C₁-C₄ alkyl group;a step of producing compound (3-B):

from the above-mentioned compound (2-3-B) or a salt thereof; a step ofproducing a compound represented by the formula (4-B):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, or a salt thereof, from theabove-mentioned compound (3-B);a step of producing a compound represented by the formula (5-B):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, from the above-mentioned compound(4-B) or a salt thereof;a step of producing a compound represented by the formula (6-B):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, from the above-mentioned compound(5-B);a step of producing a compound represented by the formula (8):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, from the above-mentioned compound(6-B); anda step of producing the above-mentioned compound (10) or a salt thereoffrom the above-mentioned compound (8).[18] The production method of the above-mentioned [17], which furthercomprisesa step of producing a compound represented by the formula (2-B):

wherein X²⁰⁰ is a halogen atom, or a salt thereof, from compound (1-B):

or a salt thereof;a step of producing a compound represented by the formula (2-1-B):

wherein R³⁰⁰ is a C₁-C₄ alkyl group, and X²⁰⁰ is a halogen atom, fromthe above-mentioned compound (2-B) or a salt thereof; and a step ofproducing a compound represented by the formula (2-2-B):

wherein R³⁰⁰ is a C₁-C₄ alkyl group, from the above-mentioned compound(2-1-B).[19] A compound represented by the formula (2-B):

wherein X²⁰⁰ is a halogen atom, or a salt thereof.[20] A compound represented by the formula (2-1):

wherein R is a fluorine atom or a methoxy group, R³⁰⁰ is a C₁-C₄ alkylgroup, and X²⁰⁰ is a halogen atom.[21] A compound represented by the formula (3):

wherein R is a fluorine atom or a methoxy group.[22] A compound represented by the formula (4):

wherein R is a fluorine atom or a methoxy group, and R¹⁰⁰ is a C₁-C₄alkyl group, or a salt thereof.[23] A compound represented by the formula (4-1)

wherein R is a fluorine atom or a methoxy group, and R¹⁰⁰ is a C₁-C₄alkyl group (hereinafter sometimes to be abbreviated as compound (4-1)),or a salt thereof.[24] A compound represented by the formula (4-2-B):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group (hereinafter sometimes to beabbreviated as compound (4-2-B)), or a salt thereof.[25] Use of a compound represented by the formula (4-1):

wherein R is a fluorine atom or a methoxy group, and R¹⁰⁰ is a C₁-C₄alkyl group, or a salt thereof, for the production of a compoundrepresented by the formula (4):

wherein R is a fluorine atom or a methoxy group, and R¹⁰⁰ is a C₁-C₄alkyl group, or a salt thereof.[26] Use of a compound represented by the formula (4-2-B):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, or a salt thereof, for theproduction of a compound represented by the formula (4-B):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, or a salt thereof.[27] Use of a compound represented by the formula (3):

wherein R is a fluorine atom or a methoxy group, and a compoundrepresented bythe formula (4-1):

wherein R is a fluorine atom or a methoxy group, and R¹⁰⁰ is a C₁-C₄alkyl group (hereinafter sometimes to be abbreviated as compound (4-1)),or a salt thereof, for the production of a compound represented by theformula (4):

wherein R is a fluorine atom or a methoxy group, and R¹⁰⁰ is a C₁-C₄alkyl group, or a salt thereof.[28] Use of compound (3-B):

and a compound represented by the formula (4-2-B):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, or a salt thereof, for theproduction of a compound represented by the formula (4-B):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, or a salt thereof.[29] A compound represented by the formula (5):

wherein R is a fluorine atom or a methoxy group, and R¹⁰⁰ is a C₁-C₄alkyl group.[30] A compound represented by the formula (6):

wherein R is a fluorine atom or a methoxy group, and R¹⁰⁰ is a C₁-C₄alkyl group.[31] A compound represented by the formula (7):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, and R²⁰⁰ is a hydroxyl-protectinggroup.[32] A compound represented by the formula (9):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, and R²⁰⁰ is a hydroxyl-protectinggroup.[33] A compound represented by the formula (8):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group.[34] A compound represented by the formula [I]:

whereinR^(C1) is a hydrogen atom or a carboxyl-protecting group,X¹ is a halogen atom,R⁴ and R⁶ are the same or different and each is a group selected fromgroup A:

-   -   cyano group, phenyl group, nitro group, halogen atom, C₁₋₄ alkyl        group, halo C₁₋₄ alkyl group, halo C₁₋₄ alkyloxy group,        —OR^(a1), —SR^(a1), —NR^(a1)R^(a2), —CONR^(a1)R^(a2),        —SO₂NR^(a1)R^(a2), —COR^(a3), —NR^(a1)COR^(a3), —SO₂R^(a3),        —NR^(a1)SO₂R^(a3), —COOR^(a1) and —NR^(a2)COOR^(a3)        -   wherein R^(a1) and R^(a2) are the same or different and each            is a hydrogen atom, a C₁₋₄ alkyl group or a benzyl group,            and R^(a3) is a C₁₋₄ alkyl group,            R⁵ is a hydrogen atom or a group selected from the            above-mentioned group A,            R⁴ and R⁵ in combination optionally form a fused ring            together with a benzene ring bonded thereto,            m is 0, 1, 2 or 3, and when m is 2 or 3, each R⁶ may be the            same or different,            R³¹ is a hydrogen atom, a cyano group, a hydroxy group, an            amino group, a nitro group, a halogen atom, a C₁₋₄ alkyl            group, a C₁₋₄ alkoxy group, a C₁₋₄ alkylsulfanyl group, a            halo C₁₋₄ alkyl group or a halo C₁₋₄ alkyloxy group,            R³² and R³³ are the same or different and each is (1) a            hydrogen atom, (2) a cyano group, (3) a nitro group, (4) a            halogen atom, (5) a C₃₋₁₀ carbon ring group optionally            substituted by 1 to 5 substituents selected from the            above-mentioned group A, (6) a heterocyclic group optionally            substituted by 1 to 5 substituents selected from the            above-mentioned group A (wherein the heterocyclic group is a            saturated or unsaturated ring containing, besides carbon            atom, at least one hetero atom selected from nitrogen atom,            oxygen atom and sulfur atom), (7) a C₁₋₁₀ alkyl group            optionally substituted by 1 to 3 substituents selected from            halogen atom and group B: a C₃₋₁₀ carbon ring group            optionally substituted by 1 to 5 substituents selected from            the above-mentioned group A, a heterocyclic group (as            defined above) optionally substituted by 1 to 5 substituents            selected from the above-mentioned group A, —OR^(a4),            —SR^(a4), —NR^(a4)R^(a5), —CONR^(a4)R^(a5),            —SO₂NR^(a4)R^(a5), —COR^(a6), —NR^(a4)COR^(a6), —SO₂R^(a6),            —NR^(a4)SO₂R^(a6), —COOR^(a4) and —NR^(a5)COOR^(a6)    -   wherein R^(a4) and R^(a5) are the same or different and each is        a hydrogen atom, a C₁₋₄ alkyl group, a C₃₋₁₀ carbon ring group        optionally substituted by 1 to 5 substituents selected from the        above-mentioned group A or a heterocyclic group (as defined        above) optionally substituted by 1 to 5 substituents selected        from the above-mentioned group A, R^(a6) is a C₁₋₄ alkyl group,        a C₃₋₁₀ carbon ring group optionally substituted by 1 to 5        substituents selected from the above-mentioned group A or a        heterocyclic group (as defined above) optionally substituted by        1 to 5 substituents selected from the above-mentioned group A,        (8) —OR^(a7), (9) —SR^(a7), (10) —NR^(a7)R^(a8), (11)        —NR^(a7)COR^(a9), (12) —COOR^(a10) or (13) —N═CH—NR^(a10)R^(a11)        wherein R^(a7) and R^(a8) are the same or different and each is        a hydrogen atom, a group selected from the above-mentioned group        B, or a C₁₋₁₀ alkyl group optionally substituted by 1 to 3        substituents selected from a halogen atom and the        above-mentioned group B, R^(a9) is a C₁₋₄ alkyl group, R^(a10)        and R^(a11) are the same or different and each is a hydrogen        atom or a C₁₋₄ alkyl group, or a salt thereof.        [35] The compound of the above-mentioned [34], wherein the        compound represented by the formula [I] is selected from the        group consisting of

-   5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoic acid,

-   5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoic acid methyl    ester and

-   5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoic acid ethyl    ester,

-   or a salt thereof.

A method of producing a compound represented by the formula [I]:

whereinR^(C1) is a hydrogen atom or a carboxyl-protecting group,X¹ is a halogen atom,R⁴ and R⁶ are the same or different and each is a group selected fromgroup A:

-   -   cyano group, phenyl group, nitro group, halogen atom, C₁₋₄ alkyl        group, halo C₁₋₄ alkyl group, halo C₁₋₄ alkyloxy group,        —OR^(a1), —SR^(a1), —NR^(a1)R^(a2), —CONR^(a1)R^(a2),        —SO₂NR^(a1)R^(a2), —COR^(a3), —NR^(a1)COR^(a3), —SO₂R^(a3),        —NR^(a1)SO₂R^(a3), —COOR^(a1) and —NR^(a2)COOR^(a3)        -   wherein R^(a1) and R^(a2) are the same or different and each            is a hydrogen atom, a C₁₋₄ alkyl group or a benzyl group,            and R^(a3) is a C₁₋₄ alkyl group,            R⁵ is a hydrogen atom or a group selected from the            above-mentioned group A,            R⁴ and R⁵ in combination optionally form a fused ring            together with the benzene ring bonded thereto,            m is 0, 1, 2 or 3, and when m is 2 or 3, each R⁶ may be the            same or different,            R³¹ is a hydrogen atom, a cyano group, a hydroxy group, an            amino group, a nitro group, a halogen atom, a C₁₋₄ alkyl            group, a C₁₋₄ alkoxy group, a C₁₋₄ alkylsulfanyl group, a            halo C₁₋₄ alkyl group or a halo C₁₋₄ alkyloxy group,            R³² and R³³ are the same or different and each is (1) a            hydrogen atom, (2) a cyano group, (3) a nitro group, (4) a            halogen atom, (5) a C₃₋₁₀ carbon ring group optionally            substituted by 1 to 5 substituents selected from the            above-mentioned group A, (6) a heterocyclic group optionally            substituted by 1 to 5 substituents selected from the            above-mentioned group A (wherein the heterocyclic group is a            saturated or unsaturated ring containing, besides carbon            atom, at least one hetero atom selected from nitrogen atom,            oxygen atom and sulfur atom), (7) a C₁₋₁₀ alkyl group            optionally substituted by 1 to 3 substituents selected from            halogen atom and group B:            a C₃₋₁₀ carbon ring group optionally substituted by 1 to 5            substituents selected from the above-mentioned group A, a            heterocyclic group (as defined above) optionally substituted            by 1 to 5 substituents selected from the above-mentioned            group A, —OR^(a4), —SR^(a4), —NR^(a4)R^(a5),            —CONR^(a4)R^(a5), —SO₂NR^(a4)R^(a5), —COR^(a6),            —NR^(a4)COR^(a6), —SO₂R^(a6), —NR^(a4)SO₂R^(a6), —COOR^(a4)            and —NR^(a5)COOR^(a6)    -   wherein R^(a4) and R^(a5) are the same or different and each is        a hydrogen atom, a C₁₋₄ alkyl group, a C₃₋₁₀ carbon ring group        optionally substituted by 1 to 5 substituents selected from the        above-mentioned group A or a heterocyclic group (as defined        above) optionally substituted by 1 to 5 substituents selected        from the above-mentioned group A, R^(a6) is a C₁₋₄ alkyl group,        a C₃₋₁₀ carbon ring group optionally substituted by 1 to 5        substituents selected from the above-mentioned group A or a        heterocyclic group (as defined above) optionally substituted by        1 to 5 substituents selected from the above-mentioned group A,        (8) —OR^(a7), (9) —SR^(a7), (10) —NR^(a7)R^(a8), (11)        —NR^(a7)COR^(a9), (12) —COOR^(a10) or (13) —N═CH—NR^(a10)R^(a11)    -   wherein R^(a7) and R^(a8) are the same or different and each is        a hydrogen atom, a group selected from the above-mentioned group        B or a C₁₋₁₀ alkyl group optionally substituted by 1 to 3        substituents selected from a halogen atom and the        above-mentioned group B, R^(a9) is a C₁₋₄ alkyl group, R^(a10)        and R^(a11) are the same or different and each is a hydrogen        atom or a C₁₋₄ alkyl group,        or a salt thereof, from a compound represented by the formula        [II]:

whereinR⁴ and R⁶ are the same or different and each is a group selected fromgroup A:cyano group, phenyl group, nitro group, halogen atom, C₁₋₄ alkyl group,halo C₁₋₄ alkyl group, halo C₁₋₄ alkyloxy group, —OR^(a1), SR^(a1),—NR^(a1)R^(a2), —CONR^(a1)R^(a2), —SO₂NR^(a1)R^(a2), —COR^(a3),—NR^(a1)COR^(a3), —SO₂R^(a3), —NR^(a1)SO₂R^(a3), —COOR^(a1) and—NR^(a2)COOR^(a3)

-   -   wherein R^(a1) and R^(a2) are the same or different and each is        a hydrogen atom, a C₁₋₄ alkyl group or a benzyl group, and        R^(a3) is a C₁₋₄ alkyl group,        R⁵ is a hydrogen atom or a group selected from the        above-mentioned group A,        R⁴ and R⁵ in combination optionally form a fused ring together        with the benzene ring bonded thereto,        m is 0, 1, 2 or 3, and when m is 2 or 3, each R⁶ may be the same        or different, and        X² is a halogen atom.        [37] The production method of the above-mentioned [36], which        comprises reacting a compound represented by the formula [II]:

wherein each symbol is as defined in the above-mentioned [36], with acompound represented by the formula [IV]:

wherein X³ is a halogen atom, and the other symbols are as defined inthe above-mentioned [36], in the presence of a metal atom M¹.[38] A method of producing a compound represented by the formula [III]:

wherein R¹ is a group selected from the above-mentioned group B, or aC₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituents selectedfrom halogen atom and the above-mentioned group B, and the other symbolsare as defined above, or a salt thereof, from a compound represented bythe formula [I]:

whereinR^(C1) is a hydrogen atom or a carboxyl-protecting group,X¹ is a halogen atom,R⁴ and R⁶ are the same or different and each is a group selected fromgroup A:

-   -   cyano group, phenyl group, nitro group, halogen atom, C₁₋₄ alkyl        group, halo C₁₋₄ alkyl group, halo C₁₋₄ alkyloxy group,        —OR^(a1), —SR^(a1), —NR^(a1)R^(a2), —CONR^(a1)R^(a2),        —SO₂NR^(a1)R^(a2), —COR^(a3), —NR^(a1)COR^(a3), —SO₂R^(a3),        —NR^(a1)SO₂R^(a3), —COOR^(a1) and —NR^(a2)COOR^(a3)        -   wherein R^(a1) and R^(a2) are the same or different and each            is a hydrogen atom, a C₁₋₄ alkyl group or a benzyl group,            and R^(a3) is a C₁₋₄ alkyl group,            R⁵ is a hydrogen atom or a group selected from the            above-mentioned group A,            R⁴ and R⁵ in combination optionally form a fused ring            together with the benzene ring bonded thereto,            m is 0, 1, 2 or 3, and when m is 2 or 3, each R⁶ may be the            same or different,            R³¹ is a hydrogen atom, a cyano group, a hydroxy group, an            amino group, a nitro group, a halogen atom, a C₁₋₄ alkyl            group, a C₁₋₄ alkoxy group, a C₁₋₄ alkylsulfanyl group, a            halo C₁₋₄ alkyl group or a halo C₁₋₄ alkyloxy group,            R³² and R³³ are the same or different and each is (1) a            hydrogen atom, (2) a cyano group, (3) a nitro group, (4) a            halogen atom, (5) a C₃₋₁₀ carbon ring group optionally            substituted by 1 to 5 substituents selected from the            above-mentioned group A, (6) a heterocyclic group optionally            substituted by 1 to 5 substituents selected from the            above-mentioned group A (wherein the heterocyclic group is a            saturated or unsaturated ring containing, besides carbon            atom, at least one hetero atom selected from nitrogen atom,            oxygen atom and sulfur atom, (7) a C₁₋₁₀ alkyl group            optionally substituted by 1 to 3 substituents selected from            halogen atom and group B:            a C₃₋₁₀ carbon ring group optionally substituted by 1 to 5            substituents selected from the above-mentioned group A, a            heterocyclic group (as defined above) optionally substituted            by 1 to 5 substituents selected from the above-mentioned            group A, —OR^(a4), —SR^(a4), —NR^(a4)R^(a5),            —CONR^(a4)R^(a5), —SO₂NR^(a4)R^(a5), —COR^(a6),            —NR^(a4)COR^(a6), —SO₂R^(a6), —NR^(a4)SO₂R^(a6), —COOR^(a4)            and —NR^(a5)COOR^(a6)    -   wherein R^(a4) and R^(a5) are the same or different and each is        a hydrogen atom, a C₁₋₄ alkyl group, a C₃₋₁₀ carbon ring group        optionally substituted by 1 to 5 substituents selected from the        above-mentioned group A or a heterocyclic group (as defined        above) optionally substituted by 1 to 5 substituents selected        from the above-mentioned group A, R^(a6) is a C₁₋₄ alkyl group,        a C₃₋₁₀ carbon ring group optionally substituted by 1 to 5        substituents selected from the above-mentioned group A or a        heterocyclic group (as defined above) optionally substituted by        1 to 5 substituents selected from the above-mentioned group A,        (8) —OR^(a7), (9) —SR^(a7), (10) —NR^(a7)R^(a)6, (11)        —NR^(a7)COR^(a)9, (12) —COOR^(a10) or (13) —N═CH—NR^(a10)R^(a11)    -   wherein R^(a7) and R^(a8) are the same or different and each is        a hydrogen atom, a group selected from the above-mentioned group        B, or a C₁₋₁₀ alkyl group optionally substituted by 1 to 3        substituents selected from a halogen atom and the        above-mentioned group B, R^(a9) is a C₁₋₄ alkyl group, R^(a10)        and R^(a11) are the same or different and each is a hydrogen        atom or a C₁₋₄ alkyl group.        [39] The production method of the above-mentioned [38], which        comprises a step of preparing a compound represented by the        formula [I]:

wherein each symbol is as defined in the above-mentioned [38], or a saltthereof, by reacting a compound represented by the formula [II]:

wherein X² is a halogen atom, and the other symbols are as defined inthe above-mentioned [38], with a compound represented by the formula[IV]:

wherein X³ is a halogen atom, and the other symbols are as defined inthe above-mentioned [38], in the presence of a metal atom M¹.[40] The production method of the above-mentioned [39], which furthercomprises at least one of the following steps:a step of subjecting a compound represented by the formula [I′]

wherein R^(C1′) is a carboxyl-protecting group, and the other symbolsare as defined in the above-mentioned [38], or a salt thereof, tohydrolysis to prepare a compound represented by the formula [Ia]:

wherein each symbol is as defined in the above-mentioned [38], or a saltthereof;a step of reacting a compound represented by the above-mentioned formula[Ia], or a salt thereof, with a halogenating agent to prepare a compoundrepresented by the formula [Ib]:

wherein X⁴ is a halogen atom, and the other symbols are as defined inthe above-mentioned [38];a step of reacting a compound represented by the above-mentioned formula[Ib], or a salt thereof, with a compound represented by the formula[XIIa]:

wherein R^(C2) is a carboxyl-protecting group, in the presence of abase, to prepare a compound represented by the formula [XI]:

wherein each symbol is as defined in the above-mentioned [38], or a saltthereof;a step of subjecting a compound represented by the above-mentionedformula [XI], or a salt thereof, to deacetylation to prepare a compoundrepresented by the formula [V]:

wherein each symbol is as defined in the above-mentioned [38], or a saltthereof;a step of reacting a compound represented by the above-mentioned formula[Ib], or a salt thereof, with a compound represented by the formula[XIIb]:

wherein R^(C2) is a carboxyl-protecting group and M is a metal atom M,in the presence of a base and a chelator, and treating the resultingcompound with an acid to prepare a compound represented by the formula[V]:

wherein each symbol is as defined in the above-mentioned [38], or a saltthereof;a step of reacting a compound represented by the above-mentioned formula[V], or a salt thereof, with a compound represented by the formula[XVII]:

wherein R^(C5) and R^(C6) are the same or different and each is a C₁₋₄alkyl group, or may form a 5- or 6-membered heterocycle together withthe adjacent nitrogen atom, and R^(C10) and R^(C11) are the same ordifferent and each is a C₁₋₄ alkyl group, to prepare a compoundrepresented by the formula [VI]:

wherein each symbol is as defined in the above-mentioned [38], or a saltthereof;a step of reacting a compound represented by the above-mentioned formula[VI], or a salt thereof, with a compound represented by the formula[XVI]:

R¹—NH₂  [XVI]

wherein R¹ is as defined in the above-mentioned [38], to prepare acompound represented by the formula [VII]:

wherein each symbol is as defined in the above-mentioned [38], or a saltthereof;a step of subjecting a compound represented by the above-mentionedformula [VII] to a cyclization reaction to prepare a compoundrepresented by the formula [VIII]:

wherein each symbol is as defined in the above-mentioned [38], or a saltthereof; anda step of subjecting a compound represented by the above-mentionedformula [VIII], or a salt thereof, to hydrolysis to prepare a compoundrepresented by the formula [III]:

wherein each symbol is as defined in the above-mentioned [38], or a saltthereof.[41] The production method of the above-mentioned [40], which comprisesa step of subjecting a compound represented by the above-mentionedformula [I′], or a salt thereof, to hydrolysis to prepare a compoundrepresented by the above-mentioned formula [Ia], or a salt thereof;a step of reacting a compound represented by the above-mentioned formula[Ia], or a salt thereof, with a halogenating agent to prepare a compoundrepresented by the above-mentioned formula [Ib], or a salt thereof;a step of reacting a compound represented by the above-mentioned formula[Ib], or a salt thereof, with a compound represented by theabove-mentioned formula [XIIb] in the presence of a base and a chelator,and treating the resulting compound with an acid to prepare a compoundrepresented by the above-mentioned formula [V], or a salt thereof;

a step of reacting a compound represented by the above-mentioned formula[V], or a salt thereof, with a compound represented by theabove-mentioned formula [XVII] to prepare a compound represented by theabove-mentioned formula [VI], or a salt thereof;

a step of reacting a compound represented by the above-mentioned formula[VI], or a salt thereof, with a compound represented by theabove-mentioned formula [XVI] to prepare a compound represented by theabove-mentioned formula [VII];a step of subjecting a compound represented by the above-mentionedformula [VII] to a cyclization reaction to prepare a compoundrepresented by the above-mentioned formula [VIII], or a salt thereof;anda step of subjecting a compound represented by the above-mentionedformula [VIII], or a salt thereof, to hydrolysis to prepare a compoundrepresented by the above-mentioned formula [III], or a salt thereof.[43] The production method of the above-mentioned [39], which furthercomprises at least one of the following steps:a step of subjecting a compound represented by the formula [I′]:

wherein R^(C1′) is a carboxyl-protecting group, and the other symbolsare as defined in the above-mentioned [38], or a salt thereof, tohydrolysis to prepare a compound represented by the formula [Ia]:

wherein each symbol is as defined in the above-mentioned [38], or a saltthereof;a step of reacting a compound represented by the above-mentioned formula[Ia], or a salt thereof, with a halogenating agent to prepare a compoundrepresented by the formula [Ib]:

wherein X⁴ is a halogen atom, and the other symbols are as defined inthe above-mentioned [38], or a salt thereof;a step of reacting a compound represented by the above-mentioned formula[Ib], or a salt thereof, with a compound represented by the formula[XIV]:

wherein R^(C7) is a C₁₋₄ alkyl group, R^(C8) and R^(C9) are the same ordifferent and each is a C₁₋₄ alkyl group, or may form a 5- or 6-memberedheterocycle together with the adjacent nitrogen atom, in the presence ofa base to prepare a compound represented by the formula [XIII]:

wherein each symbol is as defined in the above-mentioned [38];a step of reacting a compound represented by the above-mentioned formula[XIII] with a compound represented by the formula [XVI]:

R¹—NH₂  [XVI]

wherein R¹ is as defined in the above-mentioned [38], to prepare acompound represented by the formula [IX]:

wherein each symbol is as defined in the above-mentioned [38];a step of subjecting a compound represented by the above-mentionedformula [IX] to a cyclization reaction to prepare a compound representedby the formula [XV]:

wherein each symbol is as defined in the above-mentioned [38], or a saltthereof; anda step of subjecting a compound represented by the above-mentionedformula [XV], or a salt thereof, to hydrolysis to prepare a compoundrepresented by the formula [III]:

wherein each symbol is as defined in the above-mentioned [38], or a saltthereof.[43] The production method of the above-mentioned [42], which comprisesa step of subjecting a compound represented by the above-mentionedformula [I′], or a salt thereof, to hydrolysis to prepare a compoundrepresented by the above-mentioned formula [Ia] or a salt thereof;a step of reacting a compound represented by the above-mentioned formula[Ia], or a salt thereof, with a halogenating agent to prepare a compoundrepresented by the above-mentioned formula [Ib] or a salt thereof;a step of reacting a compound represented by the above-mentioned formula[Ib], or a salt thereof, with a compound represented by theabove-mentioned formula [XIV] in the presence of a base to prepare acompound represented by the above-mentioned formula [XIII];a step of reacting a compound represented by the above-mentioned formula[XIII] with a compound represented by the above-mentioned formula [XVI]to prepare a compound represented by the above-mentioned formula [IX];a step of subjecting a compound represented by the above-mentionedformula [IX] to a cyclization reaction to prepare a compound representedby the above-mentioned formula [XV] or a salt thereof; anda step of subjecting a compound represented by the above-mentionedformula [XV], or a salt thereof, to hydrolysis to prepare a compoundrepresented by the above-mentioned formula [III] or a salt thereof.[44] The production method of the above-mentioned [36] or [38], whereinthe compound represented by the formula [I] is5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoic acid.[45] The production method of the above-mentioned [36] or [39], whereinthe compound represented by the formula [II] is3-chloro-2-fluorobenzylchloride.

Effect of the Invention

The present invention can provide a novel compound useful as a syntheticintermediate for an anti-HIV agent (compound) having an integraseinhibitory activity, a production method of the synthetic intermediate,and a production method of an anti-HIV agent (compound) (e.g., compound(10) and the like) using the synthetic intermediate.

The present invention can provide an industrially highly valuableproduction method of an anti-HIV agent (compound). For example, usingintermediate compound (2′) [compound (2-2): compounds (2-2-A) and(2-2-B) and/or compound (2-3): compounds (2-3-A) and (2-3-B)] having amethoxy group as a synthetic intermediate for the production of compound(10), which is an anti-HIV agent (compound), a decrease in the yield dueto the final step (alkoxylation, particularly methoxylation) in theprior art and by-production of sodium fluoride can be avoided. Usingcompound (2′) in a ring-closing step, moreover, the generation ofhydrogen fluoride (HF) that causes corrosion of the production facilitycan be avoided, whereby problems in the prior art (avoidance ofdecreased yield, corrosion of production facility, etc.) can beovercome.

Further, the present invention can also provide a production method ofthe above-mentioned synthetic intermediate.

Since the above-mentioned synthetic intermediate can overcome theabove-mentioned problems in the prior art during the production of ananti-HIV agent (compound), the production method of the syntheticintermediate also has a high value for industrial application and issignificant.

Of the synthetic intermediates, compound (2′) is stable by itself, andcan tolerate severe conditions and/or long-term preservation.Furthermore, when the quality of compound (2′) can be controlled in theinitial production stage, not only the quality management in the latersteps but also the quality management of an anti-HIV agent (compound)(e.g., compound (10) and the like) can be facilitated. Therefore,compound (2′) is an extremely important intermediate compound.

Moreover, the present invention uses highly circulative compound (1) asa starting material. Thus, the production method of the presentinvention can produce an anti-HIV agent (compound) more economically,since stability of supply of the starting material can be improved.

BEST MODE FOR CARRYING OUT THE INVENTION Detailed Description of theInvention

The terms and symbols to be used in the present invention are defined inthe following.

A “halogen atom” means a fluorine atom, a chlorine atom, a bromine atomor an iodine atom.

A “C₁-C₄ alkyl group” means a straight chain or branched chain alkylgroup having 1 to 4 carbon atoms, and specific examples include methylgroup, ethyl group, propyl group, isopropyl group, butyl group, isobutylgroup, sec-butyl group and tert-butyl group.

A “hydroxyl-protecting group” means a general hydroxyl-protecting groupknown to those of ordinary skill in the art, which is introduced toprevent reaction of the hydroxyl group. Examples thereof include theprotecting groups described in Protective Groups in Organic Synthesis,published by John Wiley and Sons (1980) and the like, and specificexamples thereof include ether protecting groups such astetrahydropyranyl group, methoxymethyl group and the like; carbonateprotecting groups such as methylcarbonate group, ethylcarbonate groupand the like; silicon protecting groups such as trimethylsilyl group,tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, etc. andthe like.

R is a fluorine atom or a methoxy group.

R¹⁰⁰ is a “C₁-C₄ alkyl group”, preferably a methyl group or an ethylgroup, and particularly preferably an ethyl group.

R²⁰⁰ is a “hydroxyl-protecting group”, preferably a silicon protectinggroup, more preferably a tert-butyldimethylsilyl group.

R³⁰⁰ is a “C₁-C₄ alkyl group”, preferably a methyl group or an ethylgroup, particularly preferably a methyl group.

R⁴⁰⁰ is a hydrogen atom or a “C₁-C₄ alkyl group”, preferably a methylgroup or an ethyl group, particularly preferably a methyl group.

X¹⁰⁰ is a “halogen atom”, preferably a chlorine atom or a bromine atom.

X²⁰⁰ is a “halogen atom”, preferably a bromine atom or an iodine atom,more preferably a bromine atom.

A “metal atom M” is an alkali metal atom, and also includes a monovalention. Preferred is a sodium atom or a potassium atom, more preferably apotassium atom.

The “metal atom M¹” is a zinc atom, preferably metal zinc.

The expressions of “produced from a compound represented by the formula[I]” and “produced from a compound represented by the formula [II]” notonly mean directly producing an object compound from compound [I] orcompound [II], but also mean that some steps may be included in theproduction.

The “carboxyl-protecting group” is a substituent introduced to avoid areaction of carboxyl group, and examples thereof include a benzyl group,a methyl group, an ethyl group, an n-propyl group, an isopropyl group, atert-butyl group, a phenacyl group, a 2,2,2-trichloroethyl group, ap-nitrobenzyl group, a diphenylmethyl group, a 4-picolyl group, acyclohexyl group and the like.

The “carboxyl-protecting group” for R^(C1) is preferably a methyl group,an ethyl group, an n-propyl group, an isopropyl group or a tert-butylgroup, more preferably an ethyl group.

The “carboxyl-protecting group” for R^(C2) is preferably a methyl group,an ethyl group, an n-propyl group, an isopropyl group or a tert-butylgroup, more preferably an ethyl group.

The “halogen atom” is a fluorine atom, a chlorine atom, a bromine atomor an iodine atom and, unless otherwise specified, it is preferably afluorine atom, a chlorine atom or a bromine atom.

The “halogen atom” for R³², R³³ or R⁶ (including R^(6′), R^(6″) orR^(6′″) defined below) or group A (as defined below) is particularlypreferably a fluorine atom or a chlorine atom, and the “halogen atom”for R³² is more preferably a chlorine atom.

The “halogen atom” for R³¹, R³³, R^(6′) or R^(6′″) and the “halogenatom” of the “C₁₋₁₀ alkyl group optionally substituted by 1 to 3substituents selected from halogen atom and group B (as defined below)”for R³² or R³³ is more preferably a fluorine atom.

The “halogen atom” for R⁴ is preferably a fluorine atom or a chlorineatom, more preferably a fluorine atom.

The “halogen atom” for R⁵ is preferably a fluorine atom or a chlorineatom, more preferably a chlorine atom.

The “halogen atom” for X¹ is preferably a fluorine atom.

The “halogen atom” for X² is preferably a chlorine atom or a bromineatom, more preferably a chlorine atom.

The “halogen atom” for X³ is preferably a bromine atom.

The “halogen atom” for X⁴ is preferably a chlorine atom.

The “C₁₋₄ alkyl group” represents a straight chain or branched chainalkyl group having 1 to 4 carbon atoms. Specific examples include amethyl group, an ethyl group, a propyl group, an isopropyl group, abutyl group, an isobutyl group, a sec-butyl group and a tert-butylgroup.

The “C₁₋₄ alkyl group” for R³¹ or R^(a6) is preferably a methyl group oran ethyl group.

The “C₁₋₄ alkyl group” for R⁴, R⁵ or R⁶ (including R^(6′), R^(6″) orR^(6′″) defined below) or group A (as defined below) is preferably amethyl group, an ethyl group or an isopropyl group, more preferably amethyl group.

The “C₁₋₄ alkyl group” for R^(a1) or R^(a2) is preferably a methylgroup, an ethyl group, a propyl group or an isopropyl group, morepreferably a methyl group.

The “C₁₋₄ alkyl group” for R^(a3), R^(a9), R^(a10) or R^(a11) ispreferably a methyl group.

The “C₁₋₄ alkyl group” for R^(a4) or R^(a5) is preferably a methylgroup, an ethyl group or a tert-butyl group.

The “C₁₋₄ alkyl group” for R^(a6) is preferably a methyl group, an ethylgroup or a tert-butyl group.

The “C₁₋₄ alkyl group” for R^(C5) or R^(C6) is preferably a methylgroup, an ethyl group, a propyl group or an isopropyl group, morepreferably a methyl group. R^(C5) and R^(C6) are preferably the samealkyl groups.

The “C₁₋₄ alkyl group” for R^(C7) is preferably a methyl group, an ethylgroup, a propyl group or an isopropyl group, more preferably an ethylgroup.

The “C₁₋₄ alkyl group” for R^(C8) or R^(C9) is preferably a methylgroup, an ethyl group, a propyl group or an isopropyl group, morepreferably a methyl group. R^(C8) and R^(C9) are preferably the samealkyl groups.

The “C₁₋₄ alkyl group” for R^(C10) or R^(C11) is preferably a methylgroup, an ethyl group, a propyl group or an isopropyl group, morepreferably a methyl group. R^(C10) and R^(C11) are preferably the samealkyl groups.

The “halo C₁₋₄ alkyl group” is the above-defined “C₁₋₄ alkyl group”,which is substituted by 1 to 9, preferably 1 to 3, “halogen atom(s)”defined above.

Examples of thereof include a 2-fluoroethyl group, a 2-chloroethylgroup, a 2-bromoethyl group, a 3-fluoropropyl group, a 3-chloropropylgroup, a 4-fluorobutyl group, a 4-chlorobutyl group, a trifluoromethylgroup, a 2,2,2-trifluoroethyl group, a 3,3,3-trifluoropropyl group, a4,4,4-trifluorobutyl group, a pentafluoroethyl group, a2,2,2-trifluoro-1-trifluoromethylethyl group and the like.

The “halo C₁₋₄ alkyl group” for R³¹, R⁴, R⁵ or R⁶ (including R^(6′),R^(6″) or R^(6′″) defined below) or group A (as defined below) ispreferably a trifluoromethyl group.

The “C₁₋₄ alkoxy group” is an alkyloxy group wherein the alkyl moiety isthe above-defined “C₁₋₄ alkyl group”, specifically a methoxy group, anethoxy group, a propoxy group, an isopropoxy group, a butoxy group, anisobutoxy group or a tert-butoxy group.

The “C₁₋₄ alkoxyl group” for R³¹ is preferably a methoxy group.

The “C₁₋₄ alkylsulfanyl group” is an alkylsulfanyl group wherein thealkyl moiety is the above-defined “C₁₋₄ alkyl group”, specifically amethylsulfanyl group, an ethylsulfanyl group, a propylsulfanyl group, anisopropylsulfanyl group, a butylsulfanyl group, an isobutylsulfanylgroup or a tert-butylsulfanyl group.

The “C₁₋₄ alkylsulfanyl group” for R³¹ is preferably a methylsulfanylgroup.

The “halo C₁₋₄ alkyloxy group” is a haloalkyloxy group wherein thehaloalkyl moiety is the above-defined “halo C₁₋₄ alkyl group”.

Specific examples include a 2-fluoroethyloxy group, a 2-chloroethyloxygroup, a 2-bromoethyloxy group, a 3-fluoropropyloxy group, a3-chloropropyloxy group, a 4-fluorobutyloxy group, a 4-chlorobutyloxygroup, a trifluoromethyloxy group, a 2,2,2-trifluoroethyloxy group, a3,3,3-trifluoropropyloxy group, a 4,4,4-trifluorobutyloxy group, apentafluoroethyloxy group, a 2,2,2-trifluoro-1-trifluoromethylethyloxygroup and the like.

The “halo C₁₋₄ alkyloxy group” for R³¹, R⁴, R⁵, R⁶, R^(6′), R^(6″)R^(6′″) or group A (as defined below) is preferably a trifluoromethyloxygroup.

The “C₃₋₁₀ carbon ring group” is a saturated or unsaturated cyclichydrocarbon group having 3 to 10 carbon atoms, and means an aryl group,a cycloalkyl group, a cycloalkenyl group or a fused ring thereof.

Examples of the “aryl group” include a C₆₋₁₀ aryl group, specifically aphenyl group, a naphthyl group, a pentalenyl group, an azulenyl groupand the like, preferably a phenyl group and a naphthyl group, andparticularly preferably a phenyl group.

Exampled of the “cycloalkyl group” include a C₃₋₁₀ cycloalkyl group,specifically a cyclopropyl group, a cyclobutyl group, a cyclopentylgroup, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, anadamantyl group, a norbornanyl group and the like, preferably acyclopropyl group, a cyclobutyl group, a cyclopentyl group and acyclohexyl group.

Examples of the “cycloalkenyl group” include a C₃₋₁₀ cycloalkenyl groupcomprising at least one, preferably 1 or 2, double bonds, specifically acyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, acyclopentadienyl group, a cyclohexenyl group, a cyclohexadienyl group(e.g., a 2,4-cyclohexadien-1-yl group, a 2,5-cyclohexadien-1-yl groupetc.), a cycloheptenyl group and a cyclooctenyl group and the like.

Examples of the ring that these “aryl group”, “cycloalkyl group” and“cycloalkenyl group” are condensed to form include an indenyl group, anindanyl group, a 1,4-dihydronaphthyl group, a 1,2,3,4-tetrahydronaphthylgroup (e.g., 1,2,3,4-tetrahydro-2-naphthyl group,5,6,7,8-tetrahydro-2-naphthyl group etc.), a perhydronaphthyl group andthe like. Preferred is a fused ring of a phenyl group and other ring, anindenyl group, an indanyl group, an 1,4-dihydronaphthyl group, an1,2,3,4-tetrahydronaphthyl group and the like, particularly preferred isan indanyl group.

The “C₃₋₁₀ carbon ring group optionally substituted by 1 to 5substituents selected from group A” is the above-defined “C₃₋₁₀ carbonring group” optionally substituted by 1 to 5, preferably 1 to 3,substituents selected from group A defined below, and includes anunsubstituted “C₃₋₁₀ carbon ring group”. In addition, the position ofsubstitution is not particularly limited as long as it is asubstitutable position.

In the specification, the “group A” is a group consisting of a cyanogroup, a phenyl group, a nitro group, the above-defined “halogen atom”,the above-defined “C₁₋₄ alkyl group”, the above-defined “halo C₁₋₄ alkylgroup”, the above-defined “halo C₁₋₄ alkyloxy group”, —OR^(a1),—SR^(a1), —NR^(a1)R^(a2), —CONR^(a1)R^(a2), —SO₂NR^(a1)R^(a2),—COR^(a3), —NR^(a1)COR^(a3), —SO₂R^(a3), —NR^(a1)SO₂R^(a3), —COOR^(a1)and —NR^(a2)COOR^(a3) wherein R^(a1) and R^(a2) are the same ordifferent and each is a hydrogen atom, the above-defined “C₁₋₄ alkylgroup” or a benzyl group, and R^(a3) is the above-defined “C₁₋₄ alkylgroup”.

Examples of “—OR^(a1)” include a hydroxy group, a methoxy group, anethoxy group, a propoxy group, an isopropoxy group, a tert-butoxy groupand the like.

Examples of the “—SR^(a1)” include a mercapto group, a methylsulfanylgroup, an ethylsulfanyl group, a propylsulfanyl group, anisopropylsulfanyl group, a tert-butylsulfanyl group and the like.

Examples of “—NR^(a1)R^(a2)” include an amino group, a methylaminogroup, an ethylamino group, a propylamino group, an isopropylaminogroup, a tert-butylamino group, a dimethylamino group, a diethylaminogroup, an N-ethyl-N-methylamino group, an N-methyl-N-propylamino group,an N-isopropyl-N-methylamino group, an N-benzyl-N-methylamino group andthe like.

Examples of “—CONR^(a1)R^(a2)” include a carbamoyl group, amethylaminocarbonyl group, an ethylaminocarbonyl group, apropylaminocarbonyl group, an isopropylaminocarbonyl group, atert-butylaminocarbonyl group, a dimethylaminocarbonyl group, adiethylaminocarbonyl group, an N-methyl-N-ethylaminocarbonyl group andthe like.

Examples of “—SO₂NR^(a1)R^(a2)” include a sulfamoyl group, amethylaminosulfonyl group, an ethylaminosulfonyl group, apropylaminosulfonyl group, an isopropylaminosulfonyl group, atert-butylaminosulfonyl group, a dimethylaminosulfonyl group, adiethylaminosulfonyl group, an N-methyl-N-ethylaminosulfonyl group andthe like.

Examples of “—COR^(a3)” include an acetyl group, a propionyl group, abutyryl group, an isobutyryl group, a pivaloyl group and the like.

Examples of “—NR^(a1)COR^(a3)” include an acetylamino group, apropionylamino group, a butyrylamino group, an isobutyrylamino group, apivaloylamino group, an N-acetyl-N-methylamino group and the like.

Examples of “—SO₂R^(a3)” include a methylsulfonyl group, anethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group,a tert-butylsulfonyl group and the like.

Examples of “—NR^(a1)SO₂R^(a3)” include a methylsulfonylamino group, anethylsulfonylamino group, a propylsulfonylamino group, anisopropylsulfonylamino group, a tert-butylsulfonylamino group, anN-methyl-N-(methylsulfonyl)amino group and the like.

Examples of “—COOR^(a1)” include a carboxyl group, a methoxycarbonylgroup, an ethoxycarbonyl group, a propoxycarbonyl group, anisopropoxycarbonyl group, a tert-butoxycarbonyl group and the like.

Examples of “—NR^(a2)COOR^(a3)” include a methoxycarbonylamino group, anethoxycarbonylamino group, a propoxycarbonylamino group, anisopropoxycarbonylamino group, a tert-butoxycarbonylamino group and thelike.

Group A preferably contains a cyano group, a phenyl group, a nitrogroup, a fluorine atom, a chlorine atom, a bromine atom, a methyl group,an ethyl group, an isopropyl group, a trifluoromethyl group, atrifluoromethyloxy group, a hydroxy group, a methoxy group, an ethoxygroup, a propoxy group, a methylsulfanyl group, an amino group, amethylamino group, an ethylamino group, an isopropylamino group, adimethylamino group, a diethylamino group, an N-ethyl-N-methylaminogroup, an N-methyl-N-propylamino group, an N-isopropyl-N-methylaminogroup, an N-benzyl-N-methylamino group, a carbamoyl group, amethylaminocarbonyl group, a dimethylaminocarbonyl group, a sulfamoylgroup, methylaminosulfonyl group, a dimethylaminosulfonyl group, anacetyl group, an acetylamino group, an N-acetyl-N-methylamino group, amethylsulfonyl group, a methylsulfonylamino group, anN-methyl-N-(methylsulfonyl)amino group, a carboxyl group, amethoxycarbonyl group, a carboxyamino group and a methoxycarbonylaminogroup.

Group A particularly preferably contains a cyano group, a phenyl group,a nitro group, a fluorine atom, a chlorine atom, a bromine atom, amethyl group, a trifluoromethyl group, a trifluoromethyloxy group, ahydroxy group, a methoxy group, an ethoxy group, a methylsulfanyl group,an amino group, a methylamino group, a dimethylamino group, adiethylamino group, an N-ethyl-N-methylamino group, anN-methyl-N-propylamino group, an N-isopropyl-N-methylamino group, anN-benzyl-N-methylamino group, a dimethylaminocarbonyl group, amethylaminosulfonyl group, a dimethylaminosulfonyl group, an acetylaminogroup, an N-acetyl-N-methylamino group, a methylsulfonyl group, anN-methyl-N-(methylsulfonyl)amino group and a carboxyl group, morepreferably contains a fluorine atom and a chlorine atom.

The number of the substituents that the above-mentioned “C₃₋₁₀ carbonring group” may have is preferably 1 to 3, and when the “C₃₋₁₀ carbonring group” is a phenyl group, preferred are 2-positionmonosubstitution, 3-position monosubstitution, 2,3-positiondisubstitution, 2,4-position disubstitution, 2,5-positiondisubstitution, 2,6-position disubstitution, 2,3,4-positiontrisubstitution, 2,3,5-position trisubstitution and 2,3,6-positiontrisubstitution, particularly preferred is 2,3-position disubstitution.

Specific examples of the “C₃₋₁₀ carbon ring group optionally substitutedby 1 to 5 substituents selected from group A” include a phenyl group, anaphthyl group, a 2-fluorophenyl group, a 2-chlorophenyl group, a2-bromophenyl group, a 3-fluorophenyl group, a 3-chlorophenyl group, a3-bromophenyl group, a 4-fluorophenyl group, a 2-nitrophenyl group, a3-nitrophenyl group, a 2-cyanophenyl group, a 3-cyanophenyl group, a2-methylphenyl group, a 3-methylphenyl group, a 4-methylphenyl group, a2-ethylphenyl group, a 3-ethylphenyl group, a 2-isopropylphenyl group, a3-isopropylphenyl group, a 2-trifluoromethylphenyl group, a3-trifluoromethylphenyl group, a 2-hydroxyphenyl group, a3-hydroxyphenyl group, a 4-hydroxyphenyl group, a 2-methoxyphenyl group,a 3-methoxyphenyl group, a 2-ethoxyphenyl group, a 3-ethoxyphenyl group,a 2-propoxyphenyl group, a 3-propoxyphenyl group, a2-(trifluoromethyl)phenyl group, a 3-(trifluoromethyl)phenyl group, a2-(trifluoromethyloxy)phenyl group, a 3-(trifluoromethyloxy)phenylgroup, a 2-methylsulfamoylphenyl group, a 3-methylsulfamoylphenyl group,a 2-aminophenyl group, a 3-aminophenyl group, a 2-(methylamino)phenylgroup, a 3-(methylamino)phenyl group, a 2-(dimethylamino)phenyl group, a3-(dimethylamino)phenyl group, a 2-(acetylamino)phenyl group, a3-(acetylamino)phenyl group, a 2-biphenyl group, a 3-biphenyl group, a2-(methylsulfonyl)phenyl group, a 3-(methylsulfonyl)phenyl group, a2-sulfamoylphenyl group, a 3-sulfamoylphenyl group, a2-(methylaminosulfonyl)phenyl group, a 3-(methylaminosulfonyl)phenylgroup, a 2-(dimethylaminosulfonyl)phenyl group, a3-(dimethylaminosulfonyl)phenyl group, a 2-(dimethylsulfonyl)phenylgroup, a 2-(methylsulfonylamino)phenyl group, a3-(methylsulfonylamino)phenyl group, a 2-carbamoylphenyl group, a3-carbamoylphenyl group, a 2-(methylcarbamoyl)phenyl group, a3-(methylcarbamoyl)phenyl group, a 2-(dimethylcarbamoyl)phenyl group, a3-(dimethylcarbamoyl)phenyl group, a 2,3-difluorophenyl group, a3,4-difluorophenyl group, a 2,3-dichlorophenyl group, a3,4-dichlorophenyl group, a 2,3-dibromophenyl group, a 3,4-dibromophenylgroup, a 2,4-difluorophenyl group, a 2,4-dichlorophenyl group, a2,5-dichlorophenyl group, a 2,6-dichlorophenyl group, a2-chloro-3-fluorophenyl group, a 2-chloro-4-fluorophenyl group, a2-chloro-5-fluorophenyl group, a 2-chloro-6-fluorophenyl group, a3-chloro-2-fluorophenyl group, a 5-chloro-2-fluorophenyl group, a5-bromo-2-chlorophenyl group, a 2-chloro-5-nitrophenyl group, a2-chloro-3-methylphenyl group, a 2-chloro-5-methylphenyl group, a2-chloro-3-(trifluoromethyl)phenyl group, a2-chloro-5-(trifluoromethyl)phenyl group, a 2-chloro-3-hydroxyphenylgroup, a 2-chloro-5-hydroxyphenyl group, a 2-chloro-3-methoxyphenylgroup, a 2-chloro-5-methoxyphenyl group, a2-chloro-3-methylsulfamoylphenyl group, a2-chloro-5-methylsulfamoylphenyl group, a2-chloro-5-methylsulfanylphenyl group, a 2-chloro-3-aminophenyl group,2-chloro-5-aminophenyl group, a 2-chloro-3-(methylamino)phenyl group, a2-chloro-5-(methylamino)phenyl group, a 2-chloro-3-(dimethylamino)phenylgroup, a 2-chloro-5-(dimethylamino)phenyl group, a2-chloro-3-(acetylamino)phenyl group, a 2-chloro-5-(acetylamino)phenylgroup, a 2-chloro-3-(methylsulfonyl)phenyl group, a2-chloro-5-(methylsulfonyl)phenyl group, a2-chloro-3-(methylsulfonylamino)phenyl group, a2-chloro-5-(methylsulfonylamino)phenyl group, a 2,3,4-trifluorophenylgroup, a 2-chloro-3,4-difluorophenyl group, a2-chloro-3,5-difluorophenyl group, a 2-chloro-3,6-difluorophenyl group,a 2-chloro-4,5-difluorophenyl group, a 2-chloro-4,6-difluorophenylgroup, a 3-chloro-2,4-difluorophenyl group, a3-chloro-2,5-difluorophenyl group, a 3-chloro-2,6-difluorophenyl group,a 2,3-dichloro-4-fluorophenyl group, a3-chloro-2-fluoro-5-trifluoromethylphenyl group, a2-chloro-3,5,6-trifluorophenyl group, a 3-chloro-2,4,5-trifluorophenylgroup, a 3-chloro-2,4,6-trifluorophenyl group, a2,3-dichloro-4,5,6-trifluorophenyl group, a3,5-dichloro-3,4,6-trifluorophenyl group, a2,6-dichloro-3,4,5-trifluorophenyl group, a perfluorophenyl group, a2-biphenylyl group, a 3-biphenylyl group, a 4-biphenylyl group, acyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexylgroup, a 2-hydroxycyclopropyl group, a 2-hydroxycyclobutyl group, a3-hydroxycyclobutyl group, a 2-hydroxycyclopentyl group, a3-hydroxycyclopentyl group, a 2-hydroxycyclohexyl group, a3-hydroxycyclohexyl group, a 4-hydroxycyclohexyl group, a 4-indanylgroup, an 1H-inden-4-yl group and the like.

Preferably is a 2-chlorophenyl group, a 2-bromophenyl group, a2-ethylphenyl group, a 2-trifluoromethylphenyl group, a 2-hydroxyphenylgroup, a 2-ethoxyphenyl group, a 2-(methylsulfonyl)phenyl group, a2-(dimethylaminosulfonyl)phenyl group, a 2,3-difluorophenyl group, a2,3-dichlorophenyl group, a 2-chloro-3-fluorophenyl group, a2-chloro-4-fluorophenyl group, a 2-chloro-5-fluorophenyl group, a2-chloro-6-fluorophenyl group, a 3-chloro-2-fluorophenyl group, a5-bromo-2-chlorophenyl group, a 2-chloro-3-methylphenyl group, a2-chloro-5-methylphenyl group, a 2-chloro-5-hydroxyphenyl group, a2-chloro-3-methoxyphenyl group, a 2-chloro-5-methylsulfanylphenyl group,a 2-chloro-5-(methylsulfonyl)phenyl group, a 2-chloro-3,6-difluorophenylgroup and a 3-chloro-2,6-difluorophenyl group.

More preferred are a 2,3-difluorophenyl group, a 2,3-dichlorophenylgroup, a 2-chloro-3-fluorophenyl group and a 3-chloro-2-fluorophenylgroup.

The “C₃₋₁₀ carbon ring group optionally substituted by 1 to substituentsselected from group A” for R¹ or group B (as defined below) ispreferably a phenyl group, a 3,4-dichlorophenyl group, a 2-biphenylylgroup, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, acyclohexyl group, a 2-hydroxycyclopropyl group, a 2-hydroxycyclobutylgroup, a 3-hydroxycyclobutyl group, a 2-hydroxycyclopentyl group, a3-hydroxycyclopentyl group, a 2-hydroxycyclohexyl group, a3-hydroxycyclohexyl group or a 4-hydroxycyclohexyl group, particularlypreferably a phenyl group, a 3,4-dichlorophenyl group, a 2-biphenylylgroup, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or acyclohexyl group, more preferably a phenyl group or a cyclohexyl group.

The “C₃₋₁₀ carbon ring group optionally substituted by 1 to substituentsselected from group A” for R³² or R³³ is preferably a phenyl group or acyclohexyl group.

The “heterocyclic group” means a group derived from a saturated orunsaturated (including partially or completely unsaturated) monocyclic5-membered or 6-membered heterocycle containing, besides carbon atom, atleast one, preferably 1 to 4 hetero atoms selected from nitrogen atom,oxygen atom and sulfur atom, or a fused ring of the heterocycles, or afused ring of a C₃₋₁₀ carbon ring selected from benzene, cyclopentaneand cyclohexane and the heterocycle (hereinafter sometimes to beabbreviated as fused heterocycle).

Examples of the “saturated monocyclic 5-membered or 6-memberedheterocyclic group” include a pyrrolidinyl group, a tetrahydrofurylgroup, a tetrahydrothienyl group, an imidazolidinyl group, apyrazolidinyl group, a 1,3-a dioxolanyl group, a 1,3-oxathiolanyl group,an oxazolidinyl group, a thiazolidinyl group, a piperidinyl group, apiperazinyl group, a tetrahydropyranyl group, a tetrahydrothiopyranylgroup, a dioxanyl group, a morpholinyl group, a thiomorpholinyl group, a2-oxopyrrolidinyl group, a 2-oxopiperidinyl group, a 4-oxopiperidinylgroup, a 2,6-dioxopiperidinyl group and the like. Preferred is apyrrolidinyl group, a piperidinyl group or a morpholinyl group.

Examples of the “unsaturated monocyclic 5-membered or 6-memberedheterocyclic group” include a pyrrolyl group, a furyl group, a thienylgroup, an imidazolyl group, a 1,2-dihydro-2-oxoimidazolyl group, apyrazolyl group, a diazolyl group, an oxazolyl group, an isoxazolylgroup, a thiazolyl group, an isothiazolyl group, a 1,2,4-triazolylgroup, a 1,2,3-triazolyl group, a tetrazolyl group, a 1,3,4-oxadiazolylgroup, a 1,2,4-oxadiazolyl group, a 1,3,4-thiadiazolyl group, a1,2,4-thiadiazolyl group, a furazanyl group, a pyridyl group, apyrimidinyl group, a 3,4-dihydro-4-oxopyrimidinyl group, a pyridazinylgroup, a pyrazinyl group, a 1,3,5-triazinyl group, an imidazolinylgroup, a pyrazolinyl group, an oxazolinyl group (e.g., 2-oxazolinylgroup, 3-oxazolinyl group, 4-oxazolinyl group etc.), an isoxazolinylgroup, a thiazolinyl group, an isothiazolinyl group, a pyranyl group, a2-oxopyranyl group, a 2-oxo-2,5-dihydrofuranyl group, a1,1-dioxo-1H-isothiazolyl group and the like. Preferred is a pyrrolylgroup, a furyl group, a thienyl group, an imidazolyl group, a pyrazolylgroup, an oxazolyl group, an isoxazolyl group, a thiazolyl group, anisothiazolyl group, a pyridyl group, a 2-oxo-2,5-dihydrofuranyl group ora 1,1-dioxo-1H-isothiazolyl group.

Examples of the “fused heterocycle group” include an indolyl group(e.g., 2-indolyl group, 3-indolyl group, 4-indolyl group, 7-indolylgroup etc.), an isoindolyl group, a 1,3-dihydro-1,3-dioxoisoindolylgroup, a benzofuranyl group (e.g., 2-benzofuranyl group, 4-benzofuranylgroup, 7-benzofuranyl group etc.), an indazolyl group, anisobenzofuranyl group, a benzothiophenyl group (e.g., 2-benzothiophenylgroup, 4-benzothiophenyl group, 7-benzothiophenyl group etc.), abenzoxazolyl group (e.g., 2-benzoxazolyl group, 4-benzoxazolyl group,7-benzoxazolyl group etc.), a benzimidazolyl group (e.g.,2-benzimidazolyl group, 4-benzimidazolyl group, 7-benzimidazolyl groupetc.), a benzothiazolyl group (e.g., 2-benzothiazolyl group,4-benzothiazolyl group, 7-benzothiazolyl group etc.), an indolizinylgroup, a quinolyl group, an isoquinolyl group, a1,2-dihydro-2-oxoquinolyl group, a quinazolinyl group, a quinoxalinylgroup, a cinnolinyl group, a phthalazinyl group, a quinolizinyl group, apurinyl group, a pteridinyl group, an indolinyl group, an isoindolinylgroup, a 5,6,7,8-tetrahydroquinolyl group, a 1,2,3,4-tetrahydroquinolylgroup, a 2-oxo-1,2,3,4-tetrahydroquinolyl group, a benzo[1,3]dioxolylgroup, a 3,4-methylenedioxypyridyl group, a 4,5-ethylenedioxypyrimidinylgroup, a chromenyl group, a chromanyl group, an isochromanyl group andthe like.

Preferred is a fused ring of a saturated or unsaturated monocyclic5-membered or 6-membered heterocycle and a benzene ring, specifically,an indolyl group, a benzofuranyl group, a benzothiophenyl group, abenzoxazolyl group, a benzimidazolyl group, a benzothiazolyl group, abenzo[1,3]dioxolyl group and the like.

The “heterocyclic group optionally substituted by 1 to 5 substituentsselected from group A” is the above-defined “heterocyclic group”optionally substituted by 1 to 5, preferably 1 to 3, substituentsselected from the above-defined “group A”, and includes an unsubstituted“heterocyclic group”. In addition, the position of substitution is notparticularly limited as long as it is a substitutable position.

The “heterocyclic group” is preferably a monocyclic heterocyclecontaining 1 or 2 hetero atoms, or a heterocycle which is a fused ringof the monocyclic heterocycle with a benzene ring.

Examples of the “heterocyclic group optionally substituted by 1 to 5substituents selected from group A” include a pyrrolidinyl group, apiperidinyl group, a morpholinyl group, a pyrrolyl group, a 2-pyrrolylgroup, a 3-pyrrolyl group, a 2-furyl group, a 3-furyl group, a 2-thienylgroup, a 3-thienyl group, a 4,5-dichlorothiophen-3-yl group, a2-oxo-2,5-dihydrofuran-3-yl group, a 1,1-dioxo-1H-isothiazol-5-yl group,a 4-methylthiazol-5-yl group, an imidazolyl group, a 2-imidazolyl group,a 3-imidazolyl group, a 4-imidazolyl group, a pyrazolyl group, a2-oxazolyl group, a 3-isoxazolyl group, a 2-thiazolyl group, a3-isothiazolyl group, a 2-pyridyl group, a 3-fluoropyridin-2-yl group, a3-chloropyridin-2-yl group, a 3-chloro-4-fluoropyridin-2-yl group, a3,5-dichloropyridin-2-yl group, a 3-pyridyl group, a2-fluoropyridin-3-yl group, a 2-chloropyridin-3-yl group, a2-chloro-4-fluoropyridin-3-yl group, a 2-chloro-5-fluoropyridin-3-ylgroup, a 2,5-dichloropyridin-3-yl group, a 2-chloro-6-fluoropyridin-3-ylgroup, a 2,6-dichloropyridin-3-yl group, a 4-pyridyl group, a2-fluoropyridin-4-yl group, a 2-chloropyridin-4-yl group, a2-chloro-3-fluoropyridin-4-yl group, a 2,3-difluoropyridin-4-yl group, a2,3-dichloropyridin-4-yl group, a 2,5-dichloropyridin-4-yl group, a2-chloro-6-fluoropyridin-4-yl group, a 2,6-dichloropyridin-4-yl group, a2-chloro-3,6-difluoropyridin-4-yl group, a2-chloro-3,5-difluoropyridin-4-yl group, a 2,3,6-trifluoropyridin-4-ylgroup, a 2,3,5,6-tetrafluoropyridin-4-yl group, a 2-indolyl group, a3-indolyl group, a 4-indolyl group, a 7-indolyl group, a 2-benzofuranylgroup, a 4-benzofuranyl group, a 7-benzofuranyl group, a2-benzothiophenyl group, a 4-benzothiophenyl group, a 7-benzothiophenylgroup, a 2-benzimidazolyl group, a 4-benzimidazolyl group, a2-benzoxazolyl group, a 4-benzoxazolyl group, a 7-benzoxazolyl group, a2-benzothiazolyl group, a 4-benzothiazolyl group, a 7-benzothiazolylgroup, a 2-benzo[1,3]dioxolyl group, a 4-benzo[1,3]dioxolyl group, a5-benzo[1,3]dioxolyl group and the like.

The “heterocyclic group optionally substituted by 1 to 5 substituentsselected from group A” for R¹ or group B (as defined below) ispreferably a morpholinyl group, a 4-methylthiazol-5-yl group, animidazolyl group, a 2-pyridyl group or a 2-benzothiophenyl group.

The “heterocyclic group optionally substituted by 1 to 5 substituentsselected from group A” for R³² or R³³ is preferably a pyrrolidinylgroup.

The “C₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituentsselected from halogen atom and group B (as defined below)” is a C₁₋₁₀alkyl group optionally substituted by substituent(s) selected from theabove-defined “halogen atom” and the below-defined “group B”, and may bean unsubstituted alkyl group. The alkyl moiety is a straight chain orbranched chain alkyl group having 1 to 10 carbon atoms, and specificallya methyl group, an ethyl group, a propyl group, an isopropyl group, abutyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, apentyl group, an isopentyl group, a 1-methylbutyl group, a 1-ethylpropylgroup, a 2-ethylpropyl group, a 1,1-dimethylpropyl group, a1,2-dimethylpropyl group, a tert-pentyl group, a hexyl group, anisohexyl group, a 1-methylpentyl group, a 1,1-dimethylbutyl group, a1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 1-ethylbutylgroup, a 1-ethyl-1-methylpropyl group, a 1-ethyl-2-methylpropyl group, a1,1,2-trimethylpropyl group, a 1,2,2-trimethylpropyl group, a1-ethyl-1-methylpropyl group, a heptyl group, an isoheptyl group, a1-methylhexyl group, a 1,1-dimethylpentyl group, a 1,2-dimethylpentylgroup, a 1,3-dimethylpentyl group, a 1,4-dimethylpentyl group, a1,1,2-trimethylbutyl group, a 1,1,3-trimethylbutyl group, a1,2,2-trimethylbutyl group, a 1,2,3-trimethylbutyl group, a1,3,3-trimethylbutyl group, a 1-ethylpentyl group, a1-ethyl-2-methylbutyl group, a 1-ethyl-3-methylbutyl group, a2-ethyl-1-methylbutyl group, a 1-propylbutyl group, a1-ethyl-2,2-dimethylpropyl group, a 1-isopropyl-2-methylpropyl group, a1-isopropyl-1-methylpropyl group, a 1,1-diethylpropyl group, a1,1,2,2-tetramethylpropyl group, a 1-isopropylbutyl group, a1-ethyl-1-methylbutyl group, an octyl group, a nonyl group, a decanylgroup and the like, and preferred is a straight chain or branched chainalkyl group having 1 to 6 carbon atoms, particularly preferably abranched chain alkyl group having 1 to 6 carbon atoms. In addition, theposition of substitution is not particularly limited as long as it is asubstitutable position.

The “group B” is a group containing the above-defined “C₃₋₁₀ carbon ringgroup optionally substituted by 1 to 5 substituents selected from groupA”, the above-defined “heterocyclic group optionally substituted by 1 to5 substituents selected from group A”, —OR^(a4), —SR^(a4),—NR^(a4)R^(a5), —CONR^(a4)R^(a5), —SO₂NR^(a4)R^(a5), —COR^(a6),—NR^(a4)COR^(a6), —SO₂R^(a6), —NR^(a4)SO₂R^(a6), —COOR^(a4) and—NR^(a5)COOR^(a6)

wherein R^(a4) and R^(a5) are the same or different and each is ahydrogen atom, the above-defined “C₁₋₄ alkyl group”, the above-defined“C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituentsselected from group A” or the above-defined “heterocyclic groupoptionally substituted by 1 to 5 substituents selected from group A”,and R^(a6) is the above-defined “C₁₋₄ alkyl group”, the above-defined“C₃₋₁₀ carbon ring group optionally substituted by 1 to 5 substituentsselected from group A” or the above-defined “heterocyclic groupoptionally substituted by 1 to 5 substituents selected from group A”.

Examples of “—OR^(a4)” include a hydroxy group, a methoxy group, anethoxy group, a propoxy group, an isopropoxy group, a tert-butoxy groupand the like.

Examples of “—SR^(a4)” include a mercapto group, a methylsulfanyl group,an ethylsulfanyl group, a propylsulfanyl group, an isopropylsulfanylgroup, a tert-butylsulfanyl group and the like.

Examples of “—NR^(a4)R^(a5)” include an amino group, a methylaminogroup, an ethylamino group, a propylamino group, an isopropylaminogroup, a tert-butylamino group, a dimethylamino group, a diethylaminogroup, an N-ethyl-N-methylamino group, an N-methyl-N-propylamino group,an N-isopropyl-N-methylamino group, an N-benzyl-N-methylamino group andthe like.

Examples of “—CONR^(a4)R^(a5)” include a carbamoyl group, amethylaminocarbonyl group, an ethylaminocarbonyl group, apropylaminocarbonyl group, an isopropylaminocarbonyl group, atert-butylaminocarbonyl group, a dimethylaminocarbonyl group, adiethylaminocarbonyl group, an N-methyl-N-ethylaminocarbonyl group andthe like.

Examples of “—SO₂NR^(a4)R^(a5)” include a sulfamoyl group, amethylaminosulfonyl group, an ethylaminosulfonyl group, apropylaminosulfonyl group, an isopropylaminosulfonyl group, atert-butylaminosulfonyl group, a dimethylaminosulfonyl group, adiethylaminosulfonyl group, an N-methyl-N-ethylaminosulfonyl group andthe like.

Examples of “—COR^(a6)” include an acetyl group, a propionyl group, abutyryl group, an isobutyryl group, a pivaloyl group and the like.

Examples of “—NR^(a4)COR^(a6)” include an acetylamino group, apropionylamino group, a butyrylamino group, an isobutyrylamino group, apivaloylamino group, an N-acetyl-N-methylamino group and the like.

Examples of “—SO₂R^(a6)” include a methylsulfonyl group, anethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group,a tert-butylsulfonyl group and the like.

Examples of “—NR^(a4)SO₂R^(a6)” include a methylsulfonylamino group, anethylsulfonylamino group, a propylsulfonylamino group, anisopropylsulfonylamino group, a tert-butylsulfonylamino group, anN-methyl-N-(methylsulfonyl)amino group and the like.

Examples of “—COOR^(a4)” include a carboxyl group, a methoxycarbonylgroup, an ethoxycarbonyl group, a propoxycarbonyl group, anisopropoxycarbonyl group, a tert-butoxycarbonyl group and the like.

Examples of “—NR^(a5)COOR^(a6)” include a methoxycarbonylamino group, anethoxycarbonylamino group, a propoxycarbonylamino group, anisopropoxycarbonylamino group, a tert-butoxycarbonylamino group and thelike.

Examples of the above-mentioned “C₁₋₁₀ alkyl group optionallysubstituted by 1 to 3 substituents selected from halogen atom and theabove-mentioned group B” include a methyl group, an ethyl group, apropyl group, an isopropyl group, a butyl group, an isobutyl group, asec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group,a 1-methylbutyl group, a 1-ethylpropyl group, a 2-ethylpropyl group, a1,1-dimethylpropyl group, a 1,2-dimethylpropyl group, a tert-pentylgroup, a hexyl group, an isohexyl group, a 1-methylpentyl group, a1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 1,3-dimethylbutylgroup, a 1-ethylbutyl group, a 1-ethyl-1-methylpropyl group, a1-ethyl-2-methylpropyl group, a 1,1,2-trimethylpropyl group, a1,2,2-trimethylpropyl group, a 1-ethyl-1-methylpropyl group, a heptylgroup, an isoheptyl group, a 1-methylhexyl group, a 1,1-dimethylpentylgroup, a 1,2-dimethylpentyl group, a 1,3-dimethylpentyl group, a1,4-dimethylpentyl group, a 1,1,2-trimethylbutyl group, a1,1,3-trimethylbutyl group, a 1,2,2-trimethylbutyl group, a1,2,3-trimethylbutyl group, a 1,3,3-trimethylbutyl group, a1-ethylpentyl group, a 1-ethyl-2-methylbutyl group, a1-ethyl-3-methylbutyl group, a 2-ethyl-1-methylbutyl group, a1-propylbutyl group, a 1-ethyl-2,2-dimethylpropyl group, a1-isopropyl-2-methylpropyl group, a 1-isopropyl-1-methylpropyl group, a1,1-diethylpropyl group, a 1,1,2,2-tetramethylpropyl group, a1-isopropylbutyl group, a 1-ethyl-1-methylbutyl group, an octyl group, anonyl group, a decanyl group, a fluoromethyl group, a trifluoromethylgroup, a chloroethyl group, a 2-fluoroethyl group, a 2-chloroethylgroup, a 3-fluoropropyl group, a 2-chloropropyl group, a2,2,2-trifluoroethyl group, a 2-hydroxyethyl group, a 2-hydroxypropylgroup, a 2-hydroxy-1-methylethyl group, a 2-hydroxy-1,1-dimethylethylgroup, a 1-(hydroxymethyl)propyl group, a 3-hydroxypropyl group, a2-hydroxybutyl group, a 4-hydroxybutyl group, a 2-hydroxypentyl group, a5-hydroxypentyl group, a 2,3-dihydroxypropyl group, a 2,3-dihydroxybutylgroup, a 2-hydroxy-1-(hydroxymethyl)ethyl group, a2-hydroxy-2-methylpropyl group, a 1-(hydroxymethyl)butyl group, a1-(hydroxymethyl)-2-methylpropyl group, a1-(hydroxymethyl)-2,2-dimethylpropyl group, a1-(hydroxymethyl)-2-methylbutyl group, a 2-hydroxy-1-phenylethyl group,a 2-hydroxy-2-phenylethyl group, a 1-(hydroxymethyl)-2-phenylethylgroup, a 1-(hydroxymethyl)-3-methylbutyl group, a2-ethyl-1-(hydroxymethyl)butyl group, a 3-hydroxy-1-methylpropyl group,a 1,1-dimethyl-3-hydroxypropyl group, a 1,2-dimethyl-3-hydroxypropylgroup, a 1-isopropyl-3-hydroxypropyl group, a2,2-dimethyl-1-(2-hydroxyethyl)propyl group, a 1-ethyl-3-hydroxypropylgroup, a 2-hydroxy-1-isopropylpropyl group, a1-ethyl-1-(hydroxymethyl)propyl group, a 1,1-dimethyl-2-hydroxypropylgroup, a 1,2-dimethyl-2-hydroxypropyl group, a 1-ethyl-2-hydroxypropylgroup, a 4-hydroxy-1-methylbutyl group, a2-ethyl-1-(hydroxymethyl)-2-methylbutyl group, a3,3-dimethyl-1-(hydroxymethyl)butyl group, a 1-(hydroxymethyl)pentylgroup, a 4-methyl-1-(hydroxymethyl)pentyl group, a methoxymethyl group,a 2-methoxyethyl group, a methylsulfanylmethyl group, a2-(methylsulfanyl)ethyl group, a 2-aminoethyl group, a2-(dimethylamino)ethyl group, a carboxymethyl group, a 2-carboxyethylgroup, a 2-carboxypropyl group, a 3-carboxypropyl group, acarbamoylmethyl group, a 2-carbamoylethyl group, amethylaminocarbonylmethyl group, a dimethylaminocarbonylmethyl group, a2-(phenylaminocarbonyl)ethyl group, a 2-oxopropyl group, amethylsulfonylmethyl group, a 2-(methylsulfonyl)ethyl group, asulfamoylmethyl group, methylaminosulfonylmethyl group,dimethylaminosulfonylmethyl group, a tert-butylaminosulfonylmethylgroup, a 2-(acetylamino)ethyl group, a 2-(methylsulfonylamino)ethylgroup, a 2-(ethoxycarbonylamino)ethyl group, a benzyl group, a phenethylgroup, a 3-phenylpropyl group, a 4-phenylbutyl group, a2-biphenylylmethyl group, a 3,4-dichlorobenzyl group,2-hydroxy-2-phenylethyl group, a cyclopentylmethyl group, acyclohexylmethyl group, a 2-cyclohexylethyl group, a1-cyclohexyl-2-hydroxyethyl group, a 1-cyclohexylmethyl-2-hydroxyethylgroup, a phenylaminocarbonylmethyl group, a 2-pyridin-2-ylethyl group, a2-imidazol-1-ylethyl group, a benzothiophen-2-ylmethyl group, a2-benzothiophen-2-ylethyl group, a 2-morpholinoethyl group, a2-(4-methylthiazolin-5-yl)ethyl group, a 1-carboxyethyl group, a1-carbamoylethyl group, a 1-carboxy-2-methylpropyl group, a1-carbamoyl-2-methylpropyl group, a 2-hydroxy-1-(hydroxymethyl)propylgroup, a 1-(hydroxymethyl)-2-mercaptoethyl group, a1-(hydroxymethyl)-3-(methylsulfanyl)propyl group, a2-carboxy-1-(hydroxymethyl)ethyl group, a2-carbamoyl-1-(hydroxymethyl)ethyl group, a2-(indol-3-yl)-1-(hydroxymethyl)ethyl group, a2-(imidazol-4-yl)-1-(hydroxymethyl)ethyl group, a2-(4-hydroxyphenyl)-1-(hydroxymethyl)ethyl group, a3-carbamoyl-1-(hydroxymethyl)propyl group, a5-amino-1-(hydroxymethyl)pentyl group and the like.

The “C₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituentsselected from halogen atom and the above-mentioned group B” for R¹ ispreferably a methyl group, an ethyl group, a propyl group, an isopropylgroup, a butyl group, an isobutyl group, a tert-butyl group, a2-fluoroethyl group, a 2,2,2-trifluoroethyl group, a 2-hydroxyethylgroup, a 2-hydroxypropyl group, a 2-hydroxy-1-methylethyl group, a2-hydroxy-1,1-dimethylethyl group, a 1-(hydroxymethyl)propyl group, a3-hydroxypropyl group, a 4-hydroxybutyl group, a 5-hydroxypentyl group,a 2,3-dihydroxypropyl group, a 2-hydroxy-1-(hydroxymethyl)ethyl group, a2-hydroxy-2-methylpropyl group, a 1-(hydroxymethyl)butyl group, a1-(hydroxymethyl)-2-methylpropyl group, a1-(hydroxymethyl)-2,2-dimethylpropyl group, a1-(hydroxymethyl)-2-methylbutyl group, a 2-hydroxy-1-phenylethyl group,a 2-hydroxy-2-phenylethyl group, a 1-(hydroxymethyl)-2-phenylethylgroup, a 1-(hydroxymethyl)-3-methylbutyl group, a 2-methoxyethyl group,a methylsulfanylmethyl group, a 2-(methylsulfanyl)ethyl group, a2-aminoethyl group, a 2-(dimethylamino)ethyl group, a carboxymethylgroup, a 2-carboxyethyl group, a 3-carboxypropyl group, acarbamoylmethyl group, a 2-carbamoylethyl group, amethylaminocarbonylmethyl group, a dimethylaminocarbonylmethyl group, a2-(phenylaminocarbonyl)ethyl group, a 2-oxopropyl group, amethylsulfonylmethyl group, a 2-(methylsulfonyl)ethyl group, asulfamoylmethyl group, a methylaminosulfonylmethyl group, adimethylaminosulfonylmethyl group, a tert-butylaminosulfonylmethylgroup, a 2-(acetylamino)ethyl group, a 2-(methylsulfonylamino)ethylgroup, a 2-(ethoxycarbonylamino)ethyl group, a benzyl group, a phenethylgroup, a 3-phenylpropyl group, a 4-phenylbutyl group, a2-biphenylylmethyl group, a 3,4-dichlorobenzyl group, acyclopentylmethyl group, a cyclohexylmethyl group, a1-cyclohexyl-2-hydroxyethyl group, a 1-cyclohexylmethyl-2-hydroxyethylgroup, a 2-pyridin-2-ylethyl group, a 2-imidazol-1-ylethyl group, abenzothiophen-2-ylmethyl group, a 2-morpholinoethyl group or a2-(4-methylthiazolin-5-yl)ethyl group, particularly preferably an alkylgroup branched at the 1-position and/or substituted by a hydroxy group,specifically a 2-hydroxy-1-methylethyl group, a2-hydroxy-1-(hydroxymethyl)ethyl group, a1-(hydroxymethyl)-2-methylpropyl group, a1-(hydroxymethyl)-2,2-dimethylpropyl group, a1-(hydroxymethyl)-2-methylbutyl group or a1-(hydroxymethyl)-2-phenylethyl group. When the particularly preferablesubstituent is an optically active form, an S form is more preferable.

The “C₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituentsselected from a halogen atom and the above-mentioned group B” for R¹ ismost preferably a 1-(hydroxymethyl)-2-methylpropyl group, morepreferably an S form.

The “C₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituentsselected from a halogen atom and the above-mentioned group B” for R³² orR³³ is preferably a methyl group, an ethyl group or a trifluoromethylgroup.

The “C₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituentsselected from a halogen atom and the above-mentioned group B” for R^(a7)or R^(a8) is preferably a methyl group, an ethyl group, a propyl group,an isopropyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group or acyclohexylmethyl group, more preferably a methyl group, an ethyl groupor an isopropyl group, particularly preferably a methyl group.

Examples of the “fused ring” optionally formed by R⁴ and R⁵ togetherwith a benzene ring bonded thereto include naphthalen-1-yl and the like.

The “5- or 6-membered heterocycle” optionally formed by R^(c5) andR^(c6) together with the adjacent nitrogen atom is, of theabove-mentioned “heterocyclic group”, a saturated monocyclic 5-memberedor 6-membered heterocycle containing a nitrogen atom, and specificallyincludes pyrrolidine, piperidine and the like.

The “5- or 6-membered heterocycle” optionally formed by R^(c8) andR^(c9) together with the adjacent nitrogen atom is, of theabove-mentioned “heterocyclic group”, a saturated monocyclic 5-memberedor 6-membered heterocycle containing a nitrogen atom, and specificallyincludes pyrrolidine, piperidine and the like.

m is 0, 1, 2 or 3, and when m is 2 or 3, each R⁶ may be the same ordifferent.

The group represented by the formula:

wherein R⁴, R⁵, R⁶ and m are as defined above, is preferably a grouprepresented by the formula:

wherein R^(6′), R^(6″) and R^(6′″) are the same or different and each isa hydrogen atom (i.e., when m is 0) or a group selected from and theabove-defined “group A”, and R⁴ and R⁵ are as defined above.

R⁴ is preferably a phenyl group, the above-defined “halogen atom”, theabove-defined “C₁₋₄ alkyl group”, the above-defined “halo C₁₋₄ alkyloxygroup”, the above-defined “—OR^(a1)”, the above-defined“—NR^(a1)R^(a2)”, the above-defined “—SO₂NR^(a1)R^(a2)”, theabove-defined “—NR^(a1)COR^(a3)”, the above-defined “—SO₂R^(a3)”, theabove-defined “—NR^(a1)SO₂R^(a3)” or the above-defined “—COOR^(a1)”,more preferably “halogen atom”, “C₁₋₄ alkyl group”, “halo C₁₋₄ alkyloxygroup”, “—OR^(a1)” or “—NR^(a1)R^(a2)”, particularly preferably “halogenatom”.

R⁵ is preferably a hydrogen atom, a cyano group, a nitro group, theabove-defined “halogen atom”, the above-defined “C₁₋₄ alkyl group”, theabove-defined “halo C₁₋₄ alkyl group”, the above-defined “—OR^(a1)”, theabove-defined “—SR^(a1)”, the above-defined “—NR^(a1)R^(a2)”, theabove-defined “—CONR^(a1)R^(a2)”, the above-defined “—SO₂NR^(a1)R^(a2)”or the above-defined “—NR^(a1)COR^(a3)”, more preferably a hydrogenatom, “halogen atom” or “C₁₋₄ alkyl group”, particularly preferably“halogen atom”.

R⁶ is preferably the above-defined “halogen atom”, the above-defined“C₁₋₄ alkyl group”, the above-defined “—OR^(a1)”, the above-defined“—SR^(a1)” or the above-defined “—SO₂R^(a3)”, more preferably “halogenatom”.

R^(6′) and R^(6′″) are preferably the same or different and each is ahydrogen atom or the above-defined “halogen atom”.

R^(6″) is preferably a hydrogen atom, the above-defined “halogen atom”,the above-defined “C₁₋₄ alkyl group”, the above-defined “—OR^(a1)”, theabove-defined “—SR^(a1)” or the above-defined “—SO₂R^(a3)”, morepreferably a hydrogen atom, “halogen atom”, “C₁₋₄ alkyl group” or“—SR^(a1)”, more preferably a hydrogen atom.

Preferable examples of the above-mentioned substituted phenyl groupinclude a 2-chlorophenyl group, a 2-bromophenyl group, a 2-ethylphenylgroup, a 2-hydroxyphenyl group, a 2-ethoxyphenyl group, a2,3-difluorophenyl group, a 2,3-dichlorophenyl group, a2-chloro-3-fluorophenyl group, a 2-chloro-4-fluorophenyl group, a2-chloro-5-fluorophenyl group, a 2-chloro-6-fluorophenyl group, a3-chloro-2-fluorophenyl group, a 5-bromo-2-chlorophenyl group, a2-chloro-5-methylphenyl group, a 2-chloro-5-hydroxyphenyl group, a2-chloro-5-(methylsulfonyl)phenyl group, a 2-chloro-3,6-difluorophenylgroup, a 3-chloro-2,4-difluorophenyl group, a3-chloro-2,6-difluorophenyl group, a 2-chloro-3-methylphenyl group, a3-chloro-2-methylphenyl group, a 2-chloro-3-methoxyphenyl group, a3-chloro-2-methoxyphenyl group, a 2-trifluoromethylphenyl group, a2-(trifluoromethyloxy)phenyl group, 2-(methylamino)phenyl group,2-(dimethylamino)phenyl group, a 2-(diethylamino)phenyl group, a2-(N-ethyl-N-methylamino)phenyl group, a2-(N-isopropyl-N-methylamino)phenyl group, a2-(N-benzyl-N-methylamino)phenyl group, a2-(N-acetyl-N-methylamino)phenyl group, a2-(N-methyl-N-methylsulfonylamino)phenyl group, a 2-carboxyphenyl group,a 2-biphenylyl group, a 2-(methylsulfonyl)phenyl group, a2-chloro-5-methylsulfanylphenyl group, a 2-chloro-5-methylphenyl group,a 2-(methylaminosulfonyl)phenyl group and a2-(dimethylaminosulfonyl)phenyl group.

Preferred is a 2-chlorophenyl group, a 2-bromophenyl group, a2-ethylphenyl group, a 2-hydroxyphenyl group, a 2-ethoxyphenyl group, a2,3-difluorophenyl group, a 2,3-dichlorophenyl group, a2-chloro-3-fluorophenyl group, a 2-chloro-4-fluorophenyl group, a2-chloro-5-fluorophenyl group, a 2-chloro-6-fluorophenyl group, a3-chloro-2-fluorophenyl group, a 5-bromo-2-chlorophenyl group, a2-chloro-5-methylphenyl group, a 2-chloro-5-hydroxyphenyl group, a2-chloro-5-(methylsulfonyl)phenyl group, a 2-chloro-3,6-difluorophenylgroup, a 3-chloro-2,6-difluorophenyl group, a 2-chloro-3-methylphenylgroup, a 2-chloro-3-methoxyphenyl group, a 2-trifluoromethylphenylgroup, a 2-(methylsulfonyl)phenyl group, a2-chloro-5-methylsulfanylphenyl group and a2-(dimethylaminosulfonyl)phenyl group.

More preferred is a 2,3-difluorophenyl group, a 2,3-dichlorophenylgroup, a 2-chloro-3-fluorophenyl group or a 3-chloro-2-fluorophenylgroup.

Preferable examples of R¹ include the above-defined “C₃₋₁₀ carbon ringgroup optionally substituted by 1 to 5 substituents selected from groupA”, the above-defined “heterocyclic group optionally substituted by 1 to5 substituents selected from group A”, the above-defined “—OR^(a4)”(specifically preferred is a methoxy group), the above-defined“—NR^(a4)R^(a5)” (specifically preferred is an amino group, amethylamino group, an ethylamino group and a dimethylamino group), theabove-defined “—NR^(a4)COR^(a6)” (specifically preferred is anacetylamino group), the above-defined “—NR^(a4)SO₂R^(a6)” (specificallypreferred is a methylsulfonylamino group and anN-methyl-N-(methylsulfonyl)amino group), the above-defined“—NR^(a)COOR^(a6)” (specifically preferred is a methoxycarbonylaminogroup) and the above-defined “C₁₋₁₀ alkyl group optionally substitutedby 1 to 3 substituents selected from halogen atom and theabove-mentioned group B”, more preferably “C₃₋₁₀ carbon ring groupoptionally substituted by 1 to 5 substituents selected from group A” and“C₁₋₁₀ alkyl group optionally substituted by 1 to 3 substituentsselected from halogen atom and the above-mentioned group B”, still morepreferably “C₁₋₁₀ alkyl group optionally substituted by 1 to 3substituents selected from halogen atom and the above-mentioned groupB”.

Preferable examples of R³¹ include a hydrogen atom, a cyano group, ahydroxy group, the above-defined “halogen atom” and the above-defined“C₁₋₄ alkoxy group”, more preferably a hydrogen atom, a cyano group,“halogen atom” and “C₁₋₄ alkoxy group”, still more preferably a hydrogenatom, a cyano group and “C₁₋₄ alkoxy group”, particularly preferably ahydrogen atom.

Preferable examples of R³² include a hydrogen atom, a cyano group, theabove-defined “halogen atom”, the above-defined “heterocyclic groupoptionally substituted by 1 to 5 substituents selected from group A”,the above-defined “C₁₋₁₀ alkyl group optionally substituted by 1 to 3substituents selected from halogen atom and the above-mentioned groupB”, the above-defined “—OR^(a7)”, the above-defined “—SR^(a7)”, theabove-defined “—NR^(a7)R^(a8)”, the above-defined “—COOR^(a10)” and theabove-defined “—N═CH—NR^(a10)R^(a11)”, more preferably a hydrogen atom,“—OR^(a7)”, “—SR^(a7)” and “—NR^(a7)R^(a5)”, still more preferably ahydrogen atom and “—OR^(a7)”, particularly preferably “—OR^(a7)”.

As other embodiment for R³², preferred is the above-defined “halogenatom”, the above-defined “C₁₋₁₀ alkyl group optionally substituted by 1to 3 substituents selected from halogen atom and the above-mentionedgroup B” or the above-defined “—OR^(a7)”, more preferably “—OR^(a′)”,wherein R^(a7) is preferably the above-defined “C₁₋₁₀ alkyl groupoptionally substituted by 1 to 3 substituents selected from a halogenatom and the above-mentioned group B”.

As R³³, preferred is a hydrogen atom, the above-defined “C₁₋₁₀ alkylgroup optionally substituted by 1 to 3 substituents selected fromhalogen atom and the above-mentioned group B”, the above-defined“—OR^(a7)” or the above-defined “—NR^(a7)R^(a8)”, more preferably ahydrogen atom, “—OR^(a7)” or “—NR^(a7)R^(a8)”, still more preferably ahydrogen atom or “—OR^(a7)”, particularly preferably a hydrogen atom.

One of R³² and R³³ is preferably a hydrogen atom, and the other ispreferably the above-defined “—OR^(a7)”.

It is preferable that R³¹ be a hydrogen atom and R³² or R³³ be otherthan a hydrogen atom.

R^(C1) is preferably the above-defined “carboxyl-protecting group”.Particularly, R^(C1), which is a carboxyl-protecting group, is R^(C1′).

R^(C5) and R^(C6) are the same or different and each is preferably theabove-defined “C₁₋₄ alkyl group”, more preferably the same C₁₋₄ alkylgroup.

R^(C7), R^(C8) and R^(C9) are the same or different and each ispreferably the above-defined “C₁₋₄ alkyl group”, preferably the sameC₁₋₄ alkyl group.

Compound [I] is particularly preferably5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoic acid,5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoic acid methyl esteror 5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoic acid ethylester.

Compound [II] is particularly preferably 3-chloro-2-fluorobenzylchloride.

Compound (1) [compounds (1-A) and (1-B)], compound (2) [compounds (2-A)and (2-B)], compound (2-3) [compounds (2-3-A) and (2-3-B)], compound (4)[compounds (4-A) and (4-B)], compound (4-1) [compounds (4-1-A) and(4-1-B)], compound (4-2) [compounds (4-2-A) and (4-2-B)], compound (10),compound [I] and the like to be used or produced in the presentinvention may be pharmaceutically acceptable salts (sometimes to besimply referred to as salts in the present specification).

The “salt” may be any nontoxic salt as long as it can be formed from thecompound to be used in the present invention and, for example, saltsobtained by reaction with inorganic acids such as hydrochloric acid,sulfuric acid, phosphoric acid, hydrobromic acid and the like; organicacids such as oxalic acid, malonic acid, citric acid, fumaric acid,lactic acid, malic acid, succinic acid, tartaric acid, acetic acid,trifluoroacetic acid, gluconic acid, ascorbic acid, methanesulfonicacid, benzenesulfonic acid and the like; inorganic bases such as sodiumhydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide,ammonium hydroxide and the like; organic bases such as methylamine,diethylamine, triethylamine, triethanolamine, ethylenediamine,tris(hydroxymethyl)methylamine, guanidine, choline, cinchonine and thelike; amino acid such as lysin, arginine, alanine and the like, and thelike can be mentioned. Preferably, salts obtained by reaction withinorganic acids such as hydrochloric acid, sulfuric acid, hydrobromicacid and the like; organic acids such as oxalic acid, malonic acid,citric acid, fumaric acid, acetic acid, trifluoroacetic acid,methanesulfonic acid, benzenesulfonic acid and the like; inorganic basessuch as sodium hydroxide, potassium hydroxide, calcium hydroxide,magnesium hydroxide, ammonium hydroxide and the like; organic base suchas methylamine, diethylamine, triethylamine,tris(hydroxymethyl)methylamine and the like, and the like can bementioned. The compound used in the present invention also encompasseswater-containing product, hydrate and solvate of each compound.

In addition, the compound used in the present invention may have variousisomers. For example, when a double bond is present, E form and Z formare present as geometric isomers. Moreover, tautomer can also bepresent. Further, when an optical isomer may be present as an isomer,each optical isomer and a mixture thereof are also encompassed in thepresent invention. When desired, these isomers may be optically resolvedor individually produced by a method known per se.

Accordingly, those of ordinary skill in the art should understand thatall of these isomers and mixtures thereof are encompassed in the presentinvention. The compound of the present invention is preferably isolatedand purified from various isomers, by-products, metabolites andprodrugs, and preferably has a purity of not less than 90%, morepreferably not less than 95%.

One example of the production method of the present invention isexplained in the following. However, the present invention is notlimited thereto.

Even in the absence of description in the production methods, those ofordinary skill in the art will understand that an efficient productioncan be performed by employing, where necessary, introduction of aprotecting group into a functional group, removal of the protectinggroup during workup, conversion to a desired functional group at anystage and the like.

The workup after reaction in each step can be applied by a typicalmethod, wherein isolation and purification is performed by selecting orcombining conventional methods as necessary, such as crystallization,recrystallization, distillation, partition, silica gel columnchromatography, preparative HPLC and the like.

In the following production methods and the present specification, “roomtemperature” means generally 15° C.-30° C., unless particularlydescribed.

Unless otherwise specified, the amount of the solvent to be used in thefollowing production methods and the present specification is an amountthat can be stirred in the reaction system.

In the compounds represented by the formulas (1), (2), (2-1), (2-2),(2-3), (3), (4-1), (4-2), (4), (5) and (6), when R is a methoxy group,they are compounds (1-A), (2-A), (2-1-A), (2-2-A), (2-3-A), (3-A),(4-1-A), (4-2-A), (4-A), (5-A) and (6-A), respectively, and when R is afluorine atom, they are compounds (1-B), (2-B), (2-1-B), (2-2-B),(2-3-B), (3-B), (4-1-B), (4-2-B), (4-B), (5-B) and (6-B), respectively.

The production method of compound (10) or a salt thereof, which is ananti-HIV agent (compound), from compound (1) or a salt thereof, is shownin the following scheme. Specifically, the method using compound (1-A),which is compound (1) wherein R is a methoxy group is shown.

In the above-mentioned scheme, R¹⁰⁰ is a C₁-C₄ alkyl group, R²⁰⁰ is ahydroxyl-protecting group, R³⁰⁰ is a C₁-C₄ alkyl group, X¹⁰⁰ is ahalogen atom, X²⁰⁰ is a halogen atom, and M is a metal atom M.

Step 1

Compound (2-A) or a salt thereof can be produced by reacting compound(1-A) or a salt thereof with a halogenating agent in a solvent.

Compound (1-A) and a salt thereof may be commercially available product,or can be synthesized separately according to a known technique.

Examples of the halogenating agent include brominating agents such asbromine, N-bromosuccinimide and the like, and iodinating agents such asiodine, N-iodosuccinimide and the like. A brominating agent ispreferable and bromine is more preferable.

The halogenating agent is generally 1.0 to 2.0 mol, preferably 1.0 to1.2 mol, per 1 mol of compound (1-A).

In addition, a sulfite (e.g., sodium sulfite etc.) may be added aftercompletion of the reaction, for the purpose of the treatment of the freehalogen.

The amount of the sulfite to be used is generally 0 to 1.1 mol,preferably 0 to 0.3 mol, per 1 mol of compound (1-A).

Examples of the solvent include halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; polar solvents such as N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), dimethyl sulfoxide, acetonitrile and thelike; acidic solvents such as trifluoromethanesulfonic acid, sulfuricacid, acetic acid and the like or a mixed solvent thereof and the like.An acidic solvent is preferable and acetic acid is particularlypreferable.

The reaction temperature is generally 0° C. to 50° C., preferably 15° C.to 30° C.

The reaction time is generally 1 hr to 48 hr, preferably 1 hr to 12 hr,more preferably 1 hr to 3 hr.

Step 2

Compound (2-1-A) can be obtained by subjecting a compound represented bythe formula (2-A) or a salt thereof to a carboxyl-protecting reaction ina solvent under an acidic condition.

Compound (2-A) and a salt thereof may be commercially available product,or can be synthesized separately according to a known technique.

As one example of the carboxyl-protecting reaction, an esterificationreaction is explained in the following. However, those of ordinary skillin the art will understand that the carboxyl-protecting reaction is notlimited thereto.

Examples of the acid include trifluoromethanesulfonic acid, acetic acid,sulfuric acid, concentrated sulfuric acid and the like, with preferencegiven to sulfuric acid.

The number of equivalence of the acid to be used is 0.1 to 1.0,preferably 0.2 to 0.8, per 1 equivalent of compound (2-A) or a saltthereof.

The reaction temperature is generally 0° C. to 100° C., preferably 30°C. to 80° C., particularly preferably 60° C. to 70° C.

The reaction time is generally 1 hr to 48 hr, preferably 6 hr to 12 hr.

Examples of the solvent include alcohol solvents such as methanol,ethanol, n-propanol, isopropanol, n-butanol, branched butanol and thelike, with preference given to methanol and ethanol.

Step 3

Compound (2-2-A) can be obtained by reacting compound (2-1-A) with acompound represented by the formula (8-1′):

wherein X¹⁰⁰ is a halogen atom, M¹ is a metal atom (e.g., zinc atom etc.(hereinafter sometimes to be abbreviated as compound (8-1′))in a solvent, in the presence of a catalyst, as necessary in thepresence of a ligand.

Compound (8-1′) can be synthesized separately according to ReferenceExample 1, 2 or a known technique. Compound (2-1-A) can be obtained inthe same manner as in the above-mentioned Step 2.

Specifically, a compound represented by the formula (8-1′) can beobtained by reacting, in advance, the metal atom M¹ with a halide and analkylsilyl compound in a solvent, and reacting the reaction mixture withthe compound (8-1) solution.

Compound (8-1) may be commercially available product, or can besynthesized separately according to a known technique. It is preferably3-chloro-2-fluorobenzyl chloride or 3-chloro-2-fluorobenzyl bromide.

The metal atom M¹ is generally 1 to 5 mol, preferably 1 to 1.5 mol, per1 mol of compound (8-1).

Examples of the halide include 1,2-dibromoethane and the like, withpreference given to 1,2-dibromoethane.

The amount of the halide to be used is 0.01 to 0.1 mol, preferably 0.01to 0.02 mol, per 1 mol of compound (8-1).

Examples of the alkylsilyl compound include trimethylsilyl chloride andthe like, with preference given to trimethylsilyl chloride.

The amount of the alkylsilyl compound to be used is 0.01 to 0.1 mol,preferably 0.01 to 0.02 mol, per 1 mol of compound (8-1).

Examples of the solvent include ether solvents such as 1,4-dioxane,diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran (THF) and the like;hydrocarbon solvents such as toluene, hexane and the like, and the like.Preferable examples of the solvent include ether solvent, and it isparticularly preferably THF.

The reaction temperature is generally 0° C. to 100° C., particularlypreferably 20° C. to 65° C.

The reaction time is generally 1 hr to 24 hr, preferably 1 hr to 12 hr,particularly preferably 3 hr to 8 hr.

The reaction is preferably carried out under argon atmosphere or undernitrogen atmosphere, particularly preferably under argon atmosphere.

Compound (8-1′) is particularly preferably 3-chloro-2-fluorobenzylzincbromide, 3-chloro-2-fluorobenzylzinc chloride or a tetrahydrofuransolution thereof.

The amount of compound (8-1′) to be used is generally 1 to 5 mol,preferably 1 to 2 mol, per 1 mol of compound (2-1-A).

Examples of the catalyst include palladium catalysts such asbis(dibenzylideneacetone)palladium,tris(dibenzylideneacetone)dipalladium,dichlorobis(triphenylphosphine)palladium,dichlorobis(benzonitrile)palladium, dichloroethylenediaminepalladium,palladium acetate, palladium chloride,tetrakis(triphenylphosphine)palladium,bis(triphenylphosphine)palladium(II) dichloride, palladium-carbon andthe like, nickel catalyst and the like, with preference given totris(dibenzylideneacetone)dipalladium.

Examples of the ligand include triphenylphosphine,tri(2-tolyl)phosphine, tri(2-furyl)phosphine and the like, withpreference given to triphenylphosphine.

The amount of the ligand and catalyst to be used is generally 0.01 to0.1 mol, preferably 0.02 to 0.07 mol, particularly preferably 0.02 to0.06 mol, per 1 mol of compound (2-1-A), respectively.

Examples of the solvent include hydrocarbon solvents such as toluene,xylene, hexane, heptane and the like; ester solvents such as methylacetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, isobutyl acetate and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran, anisole and the like; polarsolvents such as 1-methyl-2-pyrrolidinone, N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), dimethyl sulfoxide, acetonitrile and thelike or a mixed solvent thereof and the like. An ether solvent, polarsolvent or a mixed solvent thereof is preferable and tetrahydrofuran,1-methyl-2-pyrrolidinone or a mixed solvent thereof is more preferable.

The reaction temperature is generally 0° C. to 100° C., preferably 40°C. to 80° C., more preferably 50° C. to 70° C.

The reaction time is generally 1 hr to 24 hr, preferably 1 hr to 10 hr,more preferably 2 hr to 6 hr.

The reaction is preferably carried out under argon atmosphere or undernitrogen atmosphere, particularly preferably under nitrogen atmosphere.

When the used catalyst is removed, the reaction mixture is preferablytreated with a base such as ammonium chloride, sodium hydroxide,potassium hydroxide, lithium hydroxide, diethylenetriamine,ethylenediamine and the like, particularly preferably an aqueousammonium chloride solution or an aqueous ethylenediamine solution.

Step 4

Compound (2-3-A) or a salt thereof can be obtained by subjectingcompound (2-2-A) to hydrolysis in a solvent under a basic condition(e.g., in the presence of a base such as sodium hydroxide, potassiumhydroxide, lithium hydroxide and the like) or under an acidic condition(e.g., in the presence of an acid such as hydrochloric acid, sulfuricacid and the like).

Compound (2-2-A) can be obtained in the same manner as in theabove-mentioned Step 2.

The amount of the base to be used is generally 1 to 10 mol, preferably 1to 5 mol, particularly preferably 1 to 2 mol, per 1 mol of compound(2-2-A).

The amount of the acid to be used is not particularly limited.

The reaction conditions is preferably a basic condition, and thereaction is carried out more preferably in the presence of sodiumhydroxide, particularly preferably using an aqueous sodium hydroxidesolution.

Examples of the solvent include hydrocarbon solvents such as toluene,xylene, hexane, heptane and the like; ether solvents such as1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran,anisole and the like; alcohol solvents such as methanol, ethanol,n-propanol, isopropanol and the like; polar solvents such asN,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethylsulfoxide, acetonitrile, water and the like or a mixed solvent thereofand the like, with preference given to a mixed solvent of isopropanoland water.

The reaction temperature is generally 0° C. to 100° C., preferably 15°C. to 100° C., more preferably 50° C. to 70° C.

The reaction time is generally 1 hr to 24 hr, preferably 1 hr to 12 hr,more preferably 1 hr to 8 hr.

For the workup, a treatment with an activated carbon can be carried outfor the purpose of purification of compound (2-3-A). For example, whenthe reaction condition is a basic condition, the treatment can becarried out without any limitation on the amount of the activated carbonto be used.

Step 5

Compound (3-A) can be obtained by reacting compound (2-3-A) or a saltthereof with a chlorinating agent in a solvent according to aconventional method.

Compound (2-3-A) and a salt thereof can be obtained in the same manneras in the above-mentioned Step 4.

Examples of the chlorinating agent include oxalyl chloride, phosphorusoxychloride, thionyl chloride and the like, with preference given tothionyl chloride. When oxalyl chloride or thionyl chloride is used as achlorinating agent, a catalyst (e.g., N,N-dimethylformamide etc.) may beadded.

The amount of the chlorinating agent to be used is generally 1.0 to 1.5mol, preferably 1.0 to 1.2 mol, per 1 mol of compound (2-3-A) or a saltthereof.

Examples of the solvent include hydrocarbon solvents such as toluene,xylene, hexane, heptane and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran, anisole and the like; polarsolvents such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide(DMA), dimethyl sulfoxide, acetonitrile and the like or a mixed solventthereof and the like. A hydrocarbon solvent is preferable and toluene ismore preferable.

The reaction temperature is generally 0° C. to 100° C., preferably 60°C. to 80° C., more preferably 70° C. to 80° C.

The reaction time is generally 1 hr to 24 hr, preferably 1 hr to 10 hr,more preferably 1 hr to 5 hr.

The reaction is preferably carried out under argon atmosphere or undernitrogen atmosphere, particularly preferably under nitrogen atmosphere.

Step 6

Compound (4-A) or a salt thereof, which is a 3-ketoester, can beproduced by reacting a malonic acid monoester represented by the formula(3-1) or a salt thereof (hereinafter sometimes to be abbreviated ascompound (3-1)) with compound (3-A) in a solvent, in the presence of abase and a chelator, and treating the resulting compound with an acid.

Compound (3-A) can be obtained in the same manner as in theabove-mentioned Step 5.

In compound (3-1), M is a metal atom M.

Compound (3-1) may be commercially available product, or can besynthesized separately according to a known technique. It isparticularly preferably potassium ethyl malonate.

The amount of compound (3-1) to be used is generally 1 to mol,preferably 1.0 to 2.0 mol, per 1 mol of compound (3-A).

Examples of the base include organic bases such as triethylamine,N-methylmorpholine and the like, with preference given to triethylamine.

The amount of the base to be used is generally 1 to 10 mol, preferably2.0 to 3.0 mol, per 1 mol of compound (3-A).

Examples of the chelator include a divalent magnesium compound (e.g.,magnesium chloride) and the like, with preference given to magnesiumchloride.

The amount of the chelator to be used is generally 1 to 10 mol,preferably 2.0 to 3.0 mol, per 1 mol of compound (3-A).

Examples of the solvent include hydrocarbon solvents such as toluene,xylene, hexane, heptane and the like; ester solvents such as methylacetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, isobutyl acetate and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran, anisole and the like; polarsolvents such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide(DMA), dimethyl sulfoxide, acetonitrile and the like or a mixed solventthereof and the like. An ether solvent, an ester solvent or a mixedsolvent thereof is preferable and tetrahydrofuran, ethyl acetate or amixed solvent thereof is more preferable.

The reaction temperature is generally 0° C. to 100° C., preferably 60°C. to 80° C., more preferably 70° C. to 80° C.

The reaction time is generally 1 hr to 24 hr, preferably 2 hr to 10 hr,more preferably 2 hr to 5 hr.

Examples of the acid include acetic acid, hydrochloric acid, sulfuricacid and the like, with preference given to hydrochloric acid.

The amount of the acid to be used is not particularly limited.

The reaction temperature after the addition of the acid is generally 0°C. to 100° C., preferably 0° C. to 50° C., more preferably 15° C. to 30°C. The reaction time is generally 0.5 hr to 10 hr, preferably 0.5 hr to5 hr, more preferably 0.5 hr to 2 hr.

The reaction is preferably carried out under argon atmosphere or undernitrogen atmosphere, particularly preferably under nitrogen atmosphere.

The production process compound (4-A) or a salt thereof from compound(3-A) is shown in the following scheme.

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, R^(C2) is a carboxyl-protectinggroup.

Step 6 is, in detail, a step of producing compound (4-A) or a saltthereof via compound (4-1-A) or a salt thereof, by reacting compound(3-A) with compound (3-1), and treating the resulting compound with anacid.

Compound (4-2-A) or a salt thereof can be obtained by reacting compound(3-A) with a β-ketoester compound represented by the formula [XIIa]:

wherein R^(C2) is a carboxyl-protecting group,in a solvent in the presence of a base (Step 6-1).

Examples of the base used in Step 6-1 include magnesium compounds (e.g.,magnesium chloride etc.), barium oxide and the like, with preferencegiven to barium oxide. The amount of the base to be used is generally 1to 10 mol, preferably 1 to 2 mol, per 1 mol of compound (3-A).

Examples of the solvent used in Step 6-1 include alcohol solvents suchas methanol, ethanol, n-propanol, isopropanol and the like; hydrocarbonsolvents such as toluene, hexane, xylene and the like; halogenatedsolvents such as dichloromethane, carbon tetrachloride,1,2-dichloroethane and the like; ether solvents such as 1,4-dioxane,diethyl ether, 1,2-dimethoxyethane, THF and the like; polar solventssuch as N,N-dimethylformamide (DMF), dimethyl sulfoxide, acetonitrileand the like; water or a mixed solvent thereof and the like. A mixedsolvent of toluene and water, or ethanol is preferable and a mixedsolvent of toluene and water is more preferable.

Compound [XIIa] may be commercially available product, or can besynthesized separately according to a known technique. It isparticularly preferably ethyl acetoacetate.

The amount of compound [XIIa] to be used is generally 1 to mol,preferably 1 to 2 mol, per 1 mol of compound (3-A).

The reaction temperature of Step 6-1 is generally 0° C. to 100° C.,preferably 0° C. to 50° C., particularly preferably 00° C. to 30° C.

Furthermore, compound (4-A) or a salt thereof can be obtained bysubjecting compound (4-2-A) or a salt thereof to a deacetylationreaction in a solvent under a basic condition (e.g., in the presence ofa base such as sodium acetate, potassium acetate, sodium carbonate,lithium hydroxide and the like) or under an acidic condition (e.g., inthe presence of an acid such as hydrochloric acid, sulfuric acid oracetic acid and the like) (Step 6-2).

The amount of the base used in Step 6-2 is generally 1 to mol,preferably 2 to 4 mol, particularly preferably 3 mol, per 1 mol ofcompound (4-2-A).

The amount of the acid used in Step 6-2 is not particularly limited.

The reaction conditions of Step 6-2 is preferably a basic condition,particularly preferably in the presence of sodium acetate.

Examples of the solvent used in Step 6-2 include alcohol solvents suchas methanol, ethanol, n-propanol, isopropanol and the like; hydrocarbonsolvents such as toluene, hexane, xylene and the like; halogenatedsolvents such as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloromethane and the like; ether solvents such as 1,4-dioxane,diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like; polarsolvents such as acetonitrile and the like; water or a mixed solventthereof and the like, with preference given to a mixed solvent ofethanol and water.

The reaction temperature of Step 6-2 is generally 0° C. to 100° C.,preferably 0° C. to 50° C., particularly preferably 0° C. to 30° C.

The reaction time of Step 6-2 is generally 20 hr to 120 hr, preferably24 hr to 100 hr.

Step 6-2 can be continuously performed after the above-mentioned Step6-1 without isolation treatment of compound (4-2-A) or a salt thereofobtained in the above-mentioned Step 6-1.

In the case, the reaction condition is preferably a basic condition, andthe reaction is preferably carried out in the presence of sodiumacetate.

The amount of the base to be used is generally 1 to 10 mol, preferably 2to 4 mol, particularly preferably 3 mol, per 1 mol of compound (3-A).

The reaction temperature is generally 0° C. to 100° C., preferably 0° C.to 50° C., particularly preferably 0° C. to 30° C.

The reaction time is generally 20 hr to 120 hr, preferably 24 hr to 100hr.

Step 7

Compound (5-A) can be obtained by reacting compound (4-A) or a saltthereof with compound (9-1): N,N-dimethylformamide dimethyl acetal in asolvent.

Compound (4-A) and a salt thereof can be obtained in the same manner asin the above-mentioned Step 6.

Compound (9-1) may be commercially available product, or can besynthesized separately according to a known technique.

The amount of compound (9-1) to be used is generally 1 to 10 mol,preferably 1.0 to 2 mol, particularly preferably 1.0 to 1.5 mol, per 1mol of compound (4-A) or a salt thereof.

Examples of the solvent include hydrocarbon solvents such as toluene,xylene, hexane, heptane and the like; ester solvents such as methylacetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, isobutyl acetate and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran, anisole and the like; polarsolvents such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide(DMA), dimethyl sulfoxide, acetonitrile and the like or a mixed solventthereof and the like, with preference given to toluene.

The reaction temperature is generally 20° C. to 110° C., preferably 70°C. to 110° C., more preferably 90° C. to 100° C.

The reaction time is generally 1 hr to 48 hr, preferably 10 hr to 24 hr,more preferably 15 hr to 24 hr.

The reaction is preferably carried out under argon atmosphere or undernitrogen atmosphere, particularly preferably under nitrogen atmosphere.

Step 8

Compound (6-A) can be obtained by reacting compound (5-A) with compound(5-1):L-valinol((S)-2-amino-3-methylbutan-1-ol) in a solvent.

Step 8-1

Compound (5-A) can be obtained in the same manner as in theabove-mentioned Step 7.

Compound (5-1) may be commercially available product, or can besynthesized separately according to a known technique. The opticalpurity of compound (5-1) is not less than 95% ee, preferably not lessthan 97% ee, more preferably not less than 99% ee.

The amount of compound (5-1) to be used is generally 1 to 10 mol,preferably 1 to 2 mol, particularly preferably 1.1 to 1.3 mol, per 1 molof compound (5-A).

Examples of the solvent include hydrocarbon solvents such as toluene,xylene, hexane, heptane and the like; ester solvents such as methylacetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, isobutyl acetate and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran, anisole and the like; alcoholsolvents such as methanol, ethanol, n-propanol, isopropanol and thelike; polar solvents such as N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), dimethyl sulfoxide, acetonitrile and thelike or a mixed solvent thereof and the like, with preference given totoluene.

The reaction temperature is generally 0° C. to 100° C., preferably 0° C.to 50° C., more preferably 0° C. to 30° C.

The reaction time is generally 0.5 hr to 24 hr, preferably 0.5 hr to 12hr, more preferably 0.5 hr to 3 hr.

The reaction is preferably carried out under argon atmosphere or undernitrogen atmosphere, particularly preferably under nitrogen atmosphere.

Step 8-2

Compound (7) can be obtained directly by reacting compound (5-A) withcompound (5-1) wherein the hydroxyl group is protected by the“hydroxyl-protecting group” mentioned above in a solvent.

Compound (5-1) protected by the hydroxyl-protecting group can besynthesized separately according to a known technique. Examples of thecompound (5-1) protected by the hydroxyl-protecting group include(S)-1-(tert-butyldimethylsilanyloxymethyl)-2-methylpropylamine,(S)-2-methyl-1-(trimethylsilanyloxymethyl)propylamine,(S)-2-methyl-1-(tetrahydropyran-2-yloxymethyl)propylamine, methyl2-amino-3-methylbutylcarbonate and ethyl 2-amino-3-methylbutylcarbonate.It is preferably(S)-1-(tert-butyldimethylsilanyloxymethyl)-2-methylpropylamine,(S)-2-methyl-1-(tetrahydropyran-2-yloxymethyl)propylamine or methyl2-amino-3-methylbutylcarbonate, particularly preferably(S)-1-(tert-butyldimethylsilanyloxymethyl)-2-methylpropylamine.

The optical purity of compound (5-1) protected by thehydroxyl-protecting group is not less than 95% ee, preferably not lessthan 97% ee, more preferably not less than 99% ee.

The amount of compound (5-1) protected by the hydroxyl-protecting groupto be used is generally 1 to 10 mol, preferably 1 to 2 mol, particularlypreferably 1.1 to 1.3 mol, per 1 mol of compound (5-A).

Examples of the solvent include hydrocarbon solvents such as toluene,xylene, hexane, heptane and the like; ester solvents such as methylacetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, isobutyl acetate and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran, anisole and the like; alcoholsolvents such as methanol, ethanol, n-propanol, isopropanol and thelike; polar solvents such as N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), dimethyl sulfoxide, acetonitrile and thelike or a mixed solvent thereof and the like, with preference given totoluene.

The reaction temperature is generally 0° C. to 100° C., preferably 0° C.to 50° C., more preferably 0° C. to 30° C.

The reaction time is generally 0.5 hr to 24 hr, preferably 0.5 hr to 12hr, more preferably 0.5 hr to 3 hr.

The reaction is preferably carried out under argon atmosphere or undernitrogen atmosphere, particularly preferably under nitrogen atmosphere.

Step 9

Compound (7) can be obtained by introducing a protecting group to thehydroxyl group of compound (6-A) in a solvent according to aconventional method.

Compound (6-A) can be obtained in the same manner as in theabove-mentioned Step 8-1.

For example, when the hydroxyl-protecting group is atert-butyldimethylsilyl group, compound (7) can be obtained by adding abase and tert-butyldimethylsilyl chloride to compound (6-A) in asolvent.

The amount of the tert-butyldimethylsilyl chloride to be used isgenerally 1 to 10 mol, preferably 1 to 2 mol, particularly preferably 1to 1.3 mol, per 1 mol of compound (6-A).

Examples of the base include triethylamine, diisopropylethylamine,pyridine, imidazole and the like. It is preferably imidazole.

The amount of the base to be used is generally 1 to 10 mol, preferably 1to 2 mol, particularly preferably 1 to 1.3 mol, per 1 mol of compound(6-A).

Examples of the solvent include hydrocarbon solvents such as toluene,xylene, hexane, heptane and the like; ester solvents such as methylacetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, isobutyl acetate and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran, anisole and the like; polarsolvents such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide(DMA), dimethyl sulfoxide, acetonitrile, water and the like or a mixedsolvent thereof and the like. An ether solvent, a hydrocarbon solvent, amixed solvent thereof or the like is preferable and tetrahydrofuran,toluene, a mixed solvent thereof or the like is more preferable.

The reaction temperature is generally 0° C. to 100° C., preferably 15°C. to 70° C., more preferably 40° C. to 50° C.

The reaction time is generally 1 hr to 24 hr, preferably 1 hr to 10 hr,more preferably 1 hr to 5 hr.

The reaction is preferably carried out under argon atmosphere or undernitrogen atmosphere, particularly preferably under nitrogen atmosphere.

Step 10

Compound (9) can be obtained by subjecting compound (7) to a cyclizationreaction in a solvent. A base and an additive can be added to thereaction system.

Compound (7) can be obtained in the same manner as in theabove-mentioned Step 9 or the above-mentioned Step 8-2.

Examples of the base include sodium carbonate, potassium carbonate,sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodiumhydride, potassium hydride, 1,8-diazabicyclo[5.4.0]-7-undecene and thelike, with preference given to potassium carbonate.

The amount of the base to be used is generally 0.5 to 10 mol, preferably0.5 to 2 mol, particularly preferably 0.5 to 1 mol, per 1 mol ofcompound (7).

Examples of the additive include quaternary ammonium salts such astetra-n-butylammonium bromide and the like, quaternary phosphonium saltssuch as tetra-n-butylphosphonium bromide and the like, crown ethers suchas 18-crown-6 and the like, and the like. A quaternary ammonium salt, aquaternary phosphonium salt or a crown ether is preferable andtetra-n-butylphosphonium bromide is more preferable.

The amount of the additive to be used is generally 0.05 to mol,preferably 0.05 to 2 mol, particularly preferably 0.05 to 1.0 mol, per 1mol of compound (7).

The additive may be added during the progress of the reaction.

Examples of the solvent include hydrocarbon solvents such as toluene,xylene, hexane, heptane and the like; ester solvents such as methylacetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, isobutyl acetate and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran, anisole and the like; alcoholsolvents such as methanol, ethanol, n-propanol, isopropanol and thelike; polar solvents such as N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), dimethyl sulfoxide, acetonitrile, water andthe like or a mixed solvent thereof and the like, with preference givento toluene.

The reaction temperature is generally 20° C. to 140° C., preferably 80°C. to 120° C., more preferably 100° C. to 120° C.

The reaction time is generally 1 hr to 48 hr, preferably 4 hr to 36 hr,more preferably 8 hr to 24 hr.

The reaction is preferably carried out under argon atmosphere or undernitrogen atmosphere, particularly preferably under nitrogen atmosphere.

Step 11

Compound (10) or a salt thereof can be obtained by subjecting compound(9) to hydrolysis in a solvent under a basic condition (e.g., in thepresence of a base such as sodium hydroxide, potassium hydroxide,lithium hydroxide and the like) or under an acidic condition (e.g., inthe presence of an acid such as hydrochloric acid, sulfuric acid and thelike).

The amount of the base to be used is generally 1 to 10 mol, preferably 1to 5 mol, particularly preferably 1 to 2 mol, per 1 mol of compound (9).

The amount of the acid to be used is not particularly limited.

The reaction condition is preferably a basic condition, and the reactionis more preferably carried out in the presence of sodium hydroxide,particularly preferably using an aqueous sodium hydroxide solution.

Examples of the solvent include hydrocarbon solvents such as toluene,xylene, hexane, heptane and the like; ether solvents such as1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran,anisole and the like; alcohol solvents such as methanol, ethanol,n-propanol, isopropanol and the like; polar solvents such asN,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethylsulfoxide, acetonitrile, water and the like or a mixed solvent thereofand the like, with preference given to a mixed solvent of isopropanoland water.

The reaction temperature is generally 0° C. to 150° C., preferably 15°C. to 100° C., more preferably 65° C. to 75° C.

The reaction time is generally 1 hr to 24 hr, preferably 1 hr to 12 hr,more preferably 1 hr to 8 hr.

For the workup, a treatment with an activated carbon or extractionoperation can be carried out for the purpose of the purification ofcompound (10). For example, when the reaction condition is a basiccondition, the activated carbon treatment can be carried out without anylimitation on the amount of the activated carbon to be used. Moreover,when hydrochloric acid or the like is used in the extraction operation,the amount thereof to be used is generally 1 to 10 mol, preferably 1 to5 mol, particularly preferably 1 to 2 mol, per 1 mol of compound (9).

Examples of the solvent used in the extraction operation includehydrocarbon solvents such as toluene, xylene, hexane, heptane and thelike; ester solvents such as methyl acetate, ethyl acetate, propylacetate, isopropyl acetate, butyl acetate, isobutyl acetate and thelike; halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane and the like; ketone solvents such asacetone, methylethylketone, methylisobutylketone, methylisopropylketoneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran, anisole and the like; polarsolvents such as acetonitrile and the like or a mixed solvent thereofand the like, with preference given to toluene, heptane, methyl acetate,ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate,isobutyl acetate, acetone, methylethylketone, methylisobutylketone,methylisopropylketone and anisole.

Compound (10) or a salt thereof, which is an anti-HIV agent (compound),can be also produced using compound (1-B), which is compound (1) whereinR is a fluorine atom.

In the above-mentioned scheme, R¹⁰⁰ is a C₁-C₄ alkyl group, R³⁰⁰ is aC₁-C₄ alkyl group, X¹⁰⁰ is a halogen atom, X²⁰⁰ is a halogen atom, M isa metal atom M, R^(C2) is a carboxyl-protecting group.

Compound (2-B) or a salt thereof can be obtained by reacting compound(1-B) or a salt thereof with a halogenating agent, in the same manner asin the above-mentioned Step 1. Compound (1-B) and a salt thereof may becommercially available product, or can be synthesized separatelyaccording to a known technique.

Compound (2-1-B) can be obtained by subjecting compound (2-B) or a saltthereof to a carboxyl-protecting reaction, in the same manner as in theabove-mentioned Step 2.

Compound (2-2-B) can be obtained by reacting compound (2-1-B) withcompound (8-1′), in the same manner as in the above-mentioned Step 3.

Compound (2-3-B) or a salt thereof can be obtained by subjectingcompound (2-2-B) to hydrolysis, in the same manner as in theabove-mentioned Step 4.

Compound (3-B) can be obtained by reacting compound (2-3-B) or a saltthereof with a chlorinating agent, in the same manner as in theabove-mentioned Step 5.

Compound (4-B) or a salt thereof can be obtained via compound (4-1-B) ora salt thereof, by reacting compound (3-B) with compound (3-1), in thesame manner as in the above-mentioned Step 6, and treating the resultingcompound with an acid.

Alternatively, compound (4-B) or a salt thereof can be obtained byreacting compound (3-B) with the formula [XIIa] in a solvent, in thesame manners as in the above-mentioned Step 6-1 and Step 6-2, andsubjecting the obtained compound (4-2-B) to a deacetylation reaction.

Compound (5-B) can be obtained by reacting compound (4-B) or a saltthereof with compound (9-1), in the same manner as in theabove-mentioned Step 7.

Compound (6-B) can be obtained by reacting compound (5-B) with compound(5-1), in the same manner as in the above-mentioned Step 8-1.

Step 12

Compound (8) can be obtained by subjecting compound (6-B) to acyclization reaction in a solvent (Step 12).

A base can be added to the reaction system, as necessary.

Examples of the base include sodium carbonate, potassium carbonate,sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodiumhydride, potassium hydride, 1,8-diazabicyclo[5.4.0]-7-undecene and thelike, with preference given to potassium carbonate.

The amount of the base to be used is generally 1 to 10 mol, preferably 1to 5 mol, particularly preferably 1 to 2 mol, per 1 mol of compound(6-B).

Examples of the solvent include hydrocarbon solvents such as toluene,hexane, xylene and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloromethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran and the like; polar solvents suchas N,N-dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile and thelike; ethyl acetate or a mixed solvent thereof and the like, withpreference given to N,N-dimethylformamide.

The reaction temperature is generally room temperature to 150° C.,preferably 50° C. to 100° C. or 60° C. to 110° C.

The reaction time is generally 1 hr to 24 hr, preferably 5 hr to 12 hr,particularly preferably 8 hr to 10 hr.

Step 13

Compound (10) or a salt thereof can be obtained by subjecting compound(8) to hydrolysis in a solvent under a basic condition (e.g., in thepresence of a base such as sodium hydroxide, potassium hydroxide,lithium hydroxide and the like) or under an acidic condition (e.g., inthe presence of an acid such as hydrochloric acid, sulfuric acid and thelike).

The amount of the base to be used is generally 1 to 10 mol, preferably 1to 5 mol, particularly preferably 1 to 2 mol, per 1 mol of compound (8).

The amount of the acid to be used is not particularly limited.

The reaction condition is preferably a basic condition, and the reactionis particularly preferably carried out in the presence of sodiumhydroxide.

Examples of the solvent include alcohol solvents such as methanol,ethanol, n-propanol, isopropanol and the like; hydrocarbon solvents suchas toluene, hexane, xylene and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloromethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran and the like; polar solvents suchas N,N-dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile and thelike; water or a mixed solvent thereof and the like, with preferencegiven to a mixed solvent of ethanol and water.

The reaction temperature is preferably 0° C. to 100° C., more preferably40° C. to 60° C.

The reaction time is preferably 0.5 hr to 12 hr, preferably 0.5 hr to 3hr.

In the workup, the pH of the reaction mixture is preferably 3-5.

The obtained compound (10) can be purified by recrystallization.Examples of the solvent include hydrocarbon solvents such as toluene,xylene, hexane, heptane and the like; ester solvents such as methylacetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, isobutyl acetate and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; ketone solvents such as acetone, methylethylketone,methylisobutylketone and the like; ether solvents such as 1,4-dioxane,diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, anisole and thelike; alcohol solvents such as methanol, ethanol, n-propanol,isopropanol and the like; polar solvents such as N,N-dimethylformamide(DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide, acetonitrile,water and the like or a mixed solvent thereof and the like, withpreference given to a mixed solvent of ethanol and water, and toluene.

The production method of compound [I] and the production method ofcompound [III] from compound [I] are shown below.

Production Method-1

The production method of compound [I] or a salt thereof characterized byreacting compound [II] with compound [IV] in the presence of a metalatom M¹ is shown in the following scheme.

wherein M¹ is a metal atom such as zinc and the like, and each symbol isas defined above.

Step I

A compound represented by the formula [IIa] (hereinafter sometimes to beabbreviated as compound [IIa]) can be obtained by reacting, in advance,a metal atom with a halide and an alkylsilyl compound in a solvent, andreacting the reaction mixture with the compound [II] solution.

Compound [II] may be commercially available product, or can besynthesized separately according to a known technique. It isparticularly preferably 3-chloro-2-fluorobenzyl chloride.

The amount of the metal atom M¹ to be used is generally 1 to 5 mol,preferably 1 to 1.5 mol, per 1 mol of compound [II].

Examples of the halide include 1,2-dibromoethane and the like, withpreference given to 1,2-dibromoethane.

The amount of the halide to be used is 0.01 to 0.1 mol, preferably 0.01to 0.02 mol, per 1 mol of compound [II].

Examples of the alkylsilyl compound include trimethylsilyl chloride andthe like, with preference given to trimethylsilyl chloride.

The amount of the alkylsilyl compound to be used is 0.01 to 0.1 mol,preferably 0.01 to 0.02 mol, per 1 mol of compound [II].

Examples of the solvent include ether solvents such as 1,4-dioxane,diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran (THF) and the like;hydrocarbon solvents such as toluene, hexane and the like, and the like.Preferable examples of the solvent include ether solvents, particularlypreferably THF.

The amount of the solvent to be used is generally 1 to 20 ml, preferably2 to 5 ml, per 1 g of the halide.

The reaction temperature is generally 0° C. to 100° C., particularlypreferably 20° C. to 65° C.

The reaction time is generally 1 hr to 24 hr, preferably 1 hr to 12 hr,particularly preferably 3 hr to 8 hr.

The reaction is preferably carried out under argon atmosphere or undernitrogen atmosphere, particularly preferably under nitrogen atmosphere.

Step II

Compound [IV] can be obtained by subjecting a compound represented bythe formula [X] (hereinafter sometimes to be abbreviated as compound[X]) to a carboxyl-protecting reaction (e.g., esterification reaction)in an alcohol solvent under an acidic condition, and reacting theresulting compound with a halogenating agent.

The carboxyl-protecting reaction can be carried out according to amethod known by those of ordinary skill in the art.

As one example of the carboxyl-protecting reaction, an esterificationreaction is explained in the following. However, those of ordinary skillin the art will understand that the carboxyl-protecting reaction is notlimited thereto.

(Esterification Reaction)

Compound [X] may be commercially available product, or can besynthesized separately according to a known technique.

Examples of the acid include trifluoromethanesulfonic acid, acetic acid,sulfuric acid, concentrated sulfuric acid and the like, with preferencegiven to sulfuric acid.

The number of equivalence of the acid to be used is 0.1 to 1.0,preferably 0.2 to 0.3, relative to compound [X].

The reaction temperature is generally 0° C. to 100° C., preferably 30°C. to 80° C., particularly preferably 60° C. to 70° C.

The reaction time is generally 1 hr to 48 hr, preferably 6 hr to 12 hr.

(Halogenation)

Examples of the halogenating agent include bromine, iodine,N-bromosuccinimide, N-iodosuccinimide and the like, with preferencegiven to bromine.

The amount of the halogenating agent to be used is generally 1 to 5 mol,preferably 1 to 3 mol, per 1 mol of compound [X].

In addition, a sulfite (e.g., sodium sulfite etc.) can be added asnecessary, for the purpose of the treatment of the free halogen.

The amount of the sulfite to be used is generally 1 to 5 mol, preferably1 to 2 mol, per 1 mol of compound [X].

Examples of the solvent include alcohol solvents such as methanol,ethanol, n-propanol, isopropanol and the like; hydrocarbon solvents suchas toluene, hexane, xylene and the like; halogenated solvents such asdichloromethane, carbon tetrachloride, 1,2-dichloroethane and the like;ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane,THF and the like; polar solvents such as N,N-dimethylformamide (DMF),dimethyl sulfoxide, acetonitrile and the like, and the like. An alcoholsolvent is preferable and methanol is particularly preferable.

The amount of the solvent to be used is generally 1 to 20 ml, preferably10 to 12 ml, per 1 g of compound [X].

The reaction temperature is generally 0° C. to 100° C., preferably 20°C. to 50° C.

The reaction time is generally 1 hr to 48 hr, preferably 1 hr to 12 hr,particularly preferably 1 to 5 hr.

Step III

Compound [I] or a salt thereof can be obtained by reacting compound[IIa] with compound [IV] in a solvent in the presence of a catalyst, asnecessary, in the presence of a ligand.

The amount of compound [IIa] to be used is generally 1 to mol,preferably 1 to 2 mol, per 1 mol of compound [IV].

Examples of the catalyst include palladium catalyst such asbis(dibenzylideneacetone)palladium,tris(dibenzylideneacetone)dipalladium,dichlorobis(triphenylphosphine)palladium,dichlorobis(benzonitrile)palladium, dichloroethylenediaminepalladium,palladium acetate, palladium chloride,tetrakis(triphenylphosphine)palladium,bis(triphenylphosphine)palladium(II)dichloride, palladium-carbon and thelike, nickel catalyst and the like, with preference given totris(dibenzylideneacetone)dipalladium.

Examples of the ligand include triphenylphosphine,tri(2-tolyl)phosphine, tri(2-furyl)phosphine and the like, withpreference given to triphenylphosphine.

The amount of the ligand and catalyst to be used is generally 0.01 to0.1 mol, preferably 0.02 to 0.07 mol, particularly preferably 0.02 to0.06 mol, per 1 mol of compound [IV], respectively.

Examples of the solvent include ether solvents such as 1,4-dioxane,1,3-dioxolane, diethyl ether, 1,2-dimethoxyethane, THF and the like;hydrocarbon solvents such as toluene, hexane, xylene and the like; polarsolvents such as l-methyl-2-pyrrolidinone, N,N-dimethylformamide (DMF),dimethyl sulfoxide, acetonitrile and the like, and the like, withpreference given to 1-methyl-2-pyrrolidinone.

The amount of the solvent to be used is generally 1 to 20 ml, preferably10 to 15 ml, per 1 g of compound [IV].

The reaction temperature is generally room temperature to 100° C.,preferably 70° C. to 90° C.

The reaction time is 1 hr to 24 hr, preferably 1 hr to 6 hr.

The reaction is preferably carried out under argon atmosphere or undernitrogen atmosphere, particularly preferably under nitrogen atmosphere.

When the used catalyst is removed, the reaction mixture is preferablytreated with a base such as ammonium chloride, sodium hydroxide,potassium hydroxide, lithium hydroxide, diethylenetriamine,ethylenediamine and the like, particularly preferably an aqueousammonium chloride solution or an aqueous ethylenediamine solution.

The amount of the base to be used is not particularly limited as long asthe used catalyst can be removed.

Production Method-2

The production method of compound [III] or a salt thereof from compound[I] or a salt thereof via β-ketoester compound [V] is shown in thefollowing scheme. Compound [I′], which is compound [I] wherein R^(C1) isa carboxyl-protecting group, is used as a starting material. When R^(C1)is a hydrogen atom, compound [Ia] is used as a starting material.

wherein R^(C1′) is a carboxyl-protecting group, R^(C2) is acarboxyl-protecting group, R^(C5) and R^(C6) are the same or differentand each is a C₁₋₄ alkyl group, or optionally form, together with theadjacent nitrogen atom, a 5 or 6-membered heterocycle, R^(C10) andR^(C11) are the same or different and each is a C₁₋₄ alkyl group, X⁴ isa halogen atom, M is a metal atom M, and other symbols are as definedabove.

Step IV

Compound [Ia] or a salt thereof can be obtained by subjecting compound[I′] or a salt thereof to hydrolysis in a solvent under a basiccondition (e.g., in the presence of a base such as sodium hydroxide,potassium hydroxide, lithium hydroxide and the like) or under an acidiccondition (e.g., in the presence of an acid such as hydrochloric acid,sulfuric acid and the like). The salt of compound [Ia] is as defined forthe above-mentioned definition “pharmaceutically acceptable salt” of thecompound of the present invention.

Examples of the solvent include alcohol solvents such as methanol,ethanol, n-propanol, isopropanol and the like; hydrocarbon solvents suchas toluene, hexane, xylene and the like; halogenated solvents such asdichloromethane, carbon tetrachloride, 1,2-dichloroethane and the like;ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane,THF and the like; polar solvents such as 1-methyl-2-pyrrolidinone,N,N-dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile and thelike; water or a mixed solvent thereof and the like, with preferencegiven to a mixed solvent of 1-methyl-2-pyrrolidinone and water.

The amount of the base to be used is generally 1 to 10 mol, preferably 1to 2 mol, per 1 mol of compound [I′].

The amount of the acid to be used is not particularly limited.

The reaction condition is preferably a basic condition, and the reactionis more preferably carried out in the presence of sodium hydroxide,particularly preferably using an aqueous sodium hydroxide solution.

The reaction temperature is generally room temperature to 100° C.,preferably room temperature to 40° C.

The reaction time is generally 1 hr to 24 hr, preferably 3 hr to 5 hr.

Step V

Compound [Ib] or a salt thereof is obtained by reacting compound [Ia] ora salt thereof with a halogenating agent in a solvent according to aconventional method. The salt of compound [Ib] is as defined for theabove-mentioned definition “pharmaceutically acceptable salt” of thecompound of the present invention.

Examples of the halogenating agent include phosphorus oxychloride,oxalyl chloride, thionyl chloride and the like, with preference given tothionyl chloride.

The amount of the halogenating agent to be used is generally 1 to 10mol, preferably 1 to 2 mol, per 1 mol of compound [Ia].

When thionyl chloride is used as a halogenating agent, a base (e.g.,N,N-dimethylformamide (DMF) etc.) can be added as necessary.

The amount of the base to be used is not particularly limited.

Examples of the solvent include hydrocarbon solvents such as toluene,xylene and the like; halogenated solvents such as dichloromethane,chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; ethylacetate and the like, with preference given to toluene.

The reaction temperature is generally room temperature to 100° C.,preferably 50° C. to 100° C., particularly preferably 70° C. to 90° C.

The reaction time is generally 1 hr to 10 hr, preferably 1 hr to 3 hr.

Step VI-1

Compound [XI] or a salt thereof, which is a β-diketoester, can beobtained by reacting compound [Ib] or a salt thereof and β-ketoestercompound [XIIa] in a solvent in the presence of a base. The salt ofcompound [XI] is as defined for the above-mentioned definition“pharmaceutically acceptable salt” of the compound of the presentinvention.

Examples of the base (ligand) include magnesium compounds (e.g.,magnesium chloride etc.) or barium oxide and the like.

As the base, barium oxide is preferable

The amount of the base to be used is generally 1 to 10 mol, preferably 1to 2 mol, per 1 mol of compound [Ib].

Examples of the solvent include alcohol solvents such as methanol,ethanol, n-propanol, isopropanol and the like; hydrocarbon solvents suchas toluene, hexane, xylene and the like; halogenated solvents such asdichloromethane, carbon tetrachloride, 1,2-dichloroethane and the like;ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane,THF and the like; polar solvents such as N,N-dimethylformamide (DMF),dimethyl sulfoxide, acetonitrile and the like; water or a mixed solventthereof and the like. A mixed solvent of toluene and water, or ethanolis preferable and a mixed solvent of toluene and water is morepreferable.

Compound [XIIa] may be commercially available product, or can besynthesized separately according to a known technique. It isparticularly preferably ethyl acetoacetate.

The amount of compound [XIIa] to be used is generally 1 to mol,preferably 1 to 2 mol, per 1 mol of compound [Ib].

The reaction temperature is generally 0° C. to 100° C., preferably 0° C.to 50° C., particularly preferably 0° C. to 30° C.

Step VI-2

Compound [V] or a salt thereof, which is a β-diketoester, can beobtained by reacting compound [Ib] or a salt thereof with compound[XIIb], which is a malonic acid monoester, in a solvent in the presenceof a base and a chelator, and treating the resulting compound with anacid. The salt of compound [V] is as defined for the above-mentioneddefinition “pharmaceutically acceptable salt” of the compound of thepresent invention.

In compound [XIIb], M is a metal atom M.

Compound [XIIb] may be commercially available product, or can besynthesized separately according to a known technique. It isparticularly preferably potassium ethyl malonate.

The amount of compound [XIIb] to be used is generally 1 to mol,preferably 2 to 4 mol, per 1 mol of compound [Ib].

Examples of the base include triethylamine and the like, with preferencegiven to triethylamine.

The amount of the base to be used is generally 1 to 10 mol, preferably 2to 4 mol, per 1 mol of compound [Ib].

Examples of the chelator include magnesium compound such asmagnesium(II) chloride and the like, with preference given tomagnesium(II) chloride.

The amount of the chelator to be used is generally 1 to 10 mol,preferably 2 to 4 mol, per 1 mol of compound [Ib].

Examples of the solvent include alcohol solvents such as methanol,ethanol, n-propanol, isopropanol and the like; hydrocarbon solvents suchas toluene, hexane, xylene and the like; halogenated solvents such asdichloromethane, carbon tetrachloride, 1,2-dichloroethane and the like;ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane,THF and the like; polar solvents such as N,N-dimethylformamide (DMF),dimethyl sulfoxide, acetonitrile and the like, and the like. An ethersolvent is preferable and THF is more preferable.

Examples of the acid include acetic acid, hydrochloric acid, sulfuricacid and the like, with preference given to hydrochloric acid.

The amount of the acid to be used is not particularly limited.

The reaction temperature is generally room temperature to 100° C.,preferably 60° C. to 80° C.

The reaction time is generally 1 hr to 12 hr, preferably 3 hr to 8 hr.

Step VII

Compound [V] or a salt thereof can be obtained by subjecting compound[XI] or a salt thereof to a deacetylation reaction in a solvent under abasic condition (e.g., in the presence of a base such as sodium acetate,potassium acetate, sodium carbonate, lithium hydroxide and the like) orunder an acidic condition (e.g., in the presence of an acid such ashydrochloric acid, sulfuric acid or acetic acid and the like).

The amount of the base to be used is generally 1 to 10 mol, preferably 2to 4 mol, particularly preferably 3 mol, per 1 mol of compound [XI].

The amount of the acid to be used is not particularly limited.

The reaction condition is preferably a basic condition, and the reactionis particularly preferably carried out in the presence of sodiumacetate.

Examples of the solvent include alcohol solvents such as methanol,ethanol, n-propanol, isopropanol and the like; hydrocarbon solvents suchas toluene, hexane, xylene and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloromethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran and the like; polar solvents suchas acetonitrile and the like; water or a mixed solvent thereof and thelike.

Preferable solvent is a mixed solvent of ethanol and water.

The reaction temperature is generally 0° C. to 100° C., preferably 0° C.to 50° C., particularly preferably 0° C. to 30° C.

The reaction time is generally 20 hr to 120 hr, preferably 24 hr to 100hr.

Step VII can be continuously performed after the above-mentioned StepVI-1 without isolation treatment of compound [XI] obtained in theabove-mentioned Step VI-1.

In this case, the reaction condition is preferably a basic condition,and the reaction is particularly preferably carried out in the presenceof sodium acetate.

The amount of the base to be used is generally 1 to 10 mol, preferably 2to 4 mol, particularly preferably 3 mol, per 1 mol of compound [Ib].

The reaction temperature is generally 0° C. to 100° C., preferably 0° C.to 50° C., particularly preferably 0° C. to 30° C.

The reaction time is generally 20 hr to 120 hr, preferably 24 hr to 100hr.

Step VIII

Compound [VI] or a salt thereof can be obtained by reacting compound [V]or a salt thereof with compound [XVII] in a solvent. The salt ofcompound [VI] is as defined for the above-mentioned definition“pharmaceutically acceptable salt” of the compound of the presentinvention.

Compound [XVII] may be commercially available product, or can besynthesized separately according to a known technique. It is preferablyN,N-dimethylformamide dimethyl acetal.

The amount of compound [XVII] to be used is generally 1 to mol,preferably 1 to 10 mol, particularly preferably 1 to 2 mol, per 1 mol ofcompound [V].

Examples of the solvent include ether solvents such as 1,4-dioxane,diethyl ether, 1,2-dimethoxyethane, THF and the like; hydrocarbonsolvents such as toluene, hexane and the like, and the like, withpreference given to toluene.

The reaction temperature is generally 20° C. to 100° C., preferably 75°C. to 90° C.

The reaction time is preferably 1 hr to 24 hr, preferably 3 hr to 5 hr.

Step IX

Compound [VII] can be obtained by reacting compound [VI] or a saltthereof with compound [XVI] in a solvent.

Compound [XVI] may be commercially available product, or can besynthesized separately according to a known technique. It isparticularly preferably (S)-2-amino-3-methylbutan-1-ol.

The amount of compound [XVI] to be used is generally 1 to mol,preferably 1 to 5 mol, particularly preferably 1 to 2 mol, per 1 mol ofcompound [VI].

A base can be added to the reaction system, as necessary.

Examples of the base include triethylamine, diisopropylethylamine,pyridine, potassium carbonate and the like.

The amount of the base to be used is not particularly limited.

Examples of the solvent include hydrocarbon solvents such as toluene,hexane, xylene and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloromethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran and the like; polar solvents suchas N,N-dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile and thelike; ethyl acetate or a mixed solvent thereof and the like, withpreference given to toluene.

The reaction temperature is generally room temperature to 100° C.,preferably room temperature to 70° C., particularly preferably roomtemperature to 50° C.

The reaction time is generally 1 hr to 12 hr, preferably 1 hr to 8 hr,particularly preferably 1.5 hr to 5 hr.

The pH of the reaction system after the reaction is preferably 7 to 8.

Step X

Compound [VIII] or a salt thereof can be obtained by subjecting compound[VII] to a cyclization reaction in a solvent. The salt of compound[VIII] is as defined for the above-mentioned definition“pharmaceutically acceptable salt” of the compound of the presentinvention.

A base can be added to the reaction system, as necessary.

Examples of the base include sodium carbonate, potassium carbonate,sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodiumhydride, potassium hydride, 1,8-diazabicyclo[5.4.0]-7-undecene and thelike, with preference given to potassium carbonate.

The amount of the base to be used is generally 1 to 10 mol, preferably 1to 5 mol, particularly preferably 1 to 2 mol, per 1 mol of compound[VII].

Examples of the solvent include hydrocarbon solvents such as toluene,hexane, xylene and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloromethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran and the like; polar solvents suchas N,N-dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile and thelike; ethyl acetate or a mixed solvent thereof and the like, withpreference given to N,N-dimethylformamide.

The reaction temperature is generally room temperature to 150° C.,preferably 50° C. to 100° C. or 60° C. to 110° C.

The reaction time is generally 1 hr to 24 hr, preferably 5 hr to 12 hr,particularly preferably 8 hr to 10 hr.

Step XI

Compound [III] or a salt thereof can be obtained by subjecting compound[VIII] or a salt thereof to hydrolysis in a solvent under a basiccondition (e.g., in the presence of a base such as sodium hydroxide,potassium hydroxide, lithium hydroxide and the like) or under an acidiccondition (e.g., in the presence of an acid such as hydrochloric acid,sulfuric acid and the like). The salt of compound [III] is as definedfor the above-mentioned definition “pharmaceutically acceptable salt” ofthe compound of the present invention.

The amount of the base to be used is generally 1 to 10 mol, preferably 1to 5 mol, particularly preferably 1 to 2 mol, per 1 mol of compound[VIII].

The amount of the acid to be used is not particularly limited.

The reaction condition is preferably a basic condition, and the reactionis particularly preferably carried out in the presence of sodiumhydroxide.

Examples of the solvent include alcohol solvents such as methanol,ethanol, n-propanol, isopropanol and the like; hydrocarbon solvents suchas toluene, hexane, xylene and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloromethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran and the like; polar solvents suchas N,N-dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile and thelike; water or a mixed solvent thereof and the like, with preferencegiven to a mixed solvent of ethanol and water.

The reaction temperature is preferably 0° C. to 100° C., more preferably40° C. to 60° C.

The reaction time is preferably 0.5 hr to 12 hr, preferably 0.5 hr to 3hr.

In the workup, the pH of the reaction mixture is preferably 3-5.

Production Method-3

The production method of compound [III] or a salt thereof from compound[Ib] or a salt thereof obtained in Production method-2, via compound[XIII] (which is a 3-aminoacrylic acid ester derivative), is shown inthe following scheme.

wherein R^(C7) is a C₁₋₄ alkyl group, R^(C8) and R^(C9) are the same ordifferent and each is a C₁₋₄ alkyl group, or optionally form, togetherwith the adjacent nitrogen atom, a 5 or 6-membered heterocycle, and theother symbols are as defined above.

Step XII

Compound [XIII] can be obtained by reacting compound [Ib] or a saltthereof obtained in Step V of Production method-2 with compound [XIV] ina solvent in the presence of a base.

Compound [XIV] may be commercially available product, or can besynthesized separately according to a known technique. It isparticularly preferably ethyl 3-dimethylaminoacrylate.

The amount of compound [XIV] to be used is generally 1 to 10 mol,preferably 1 to 3 mol, particularly preferably 1 to 2 mol, per 1 mol ofcompound [Ib].

Examples of the base include triethylamine, N,N-diisopropylamine,potassium carbonate, pyridine and the like, with preference given toN,N-diisopropylamine.

The amount of the base to be used is not particularly limited.

Examples of the solvent include hydrocarbon solvents such as toluene,hexane, xylene and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, THF and the like; polar solvents such asacetonitrile and the like; ethyl acetate or a mixed solvent thereof andthe like, with preference given to toluene.

The reaction temperature is generally room temperature to 100° C.,preferably 70° C. to 80° C.

The reaction time is generally 1 hr to 12 hr, preferably 6 hr to 12 hr.

Step XIII (Similar to Step IX of Production Method-2)

Compound [IX] can be obtained by reacting compound [XIII] with compound[XVI] in a solvent.

Compound [XVI] may be commercially available product, or can besynthesized separately according to a known technique. It isparticularly preferably (S)-2-amino-3-methylbutan-1-ol.

The amount of compound [XVI] to be used is generally 1 to mol,preferably 1 to 5 mol, particularly preferably 1 to 2 mol, per 1 mol ofcompound [XIII].

A base can be added to the reaction system, as necessary.

Examples of the base include triethylamine, diisopropylethylamine,pyridine, potassium carbonate and the like.

The amount of the base to be used is not particularly limited.

Examples of the solvent include hydrocarbon solvents such as toluene,hexane, xylene and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloromethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran and the like; polar solvents suchas N,N-dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile and thelike; ethyl acetate or a mixed solvent thereof and the like, withpreference given to toluene.

The reaction temperature is generally room temperature to 100° C.,preferably room temperature to 70° C., particularly preferably roomtemperature to 50° C.

The reaction time is generally 1 hr to 12 hr, preferably 1 hr to 8 hr,particularly preferably 1.5 hr to 5 hr.

The pH of the reaction system after the reaction is preferably 7 to 8.

Step XIV (Similar to Step X of Production Method-2)

Compound [XV] or a salt thereof can be obtained by subjecting compound[IX] to a cyclization reaction in a solvent. The salt of compound [XV]is as defined for the above-mentioned definition “pharmaceuticallyacceptable salt” of the compound of the present invention.

A base can be added to the reaction system, as necessary.

Examples of the base include sodium carbonate, potassium carbonate,sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodiumhydride, potassium hydride, 1,8-diazabicyclo[5.4.0]-7-undecene and thelike, with preference given to potassium carbonate.

The amount of the base to be used is generally 1 to 10 mol, preferably 1to 5 mol, particularly preferably 1 to 2 mol, per 1 mol of compound[IX].

Examples of the solvent include hydrocarbon solvents such as toluene,hexane, xylene and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloromethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran and the like; polar solvents suchas N,N-dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile and thelike; ethyl acetate or a mixed solvent thereof and the like, withpreference given to N,N-dimethylformamide.

The reaction temperature is generally room temperature to 150° C.,preferably 50° C. to 100° C. or 60° C. to 110° C.

The reaction time is generally 1 hr to 24 hr, preferably 5 hr to 12 hr,particularly preferably 8 hr to 10 hr.

Step XV (Similar to Step XI of Production Method-2)

Compound [III] or a salt thereof can be obtained by subjecting compound[XV] or a salt thereof to hydrolysis in a solvent under a basiccondition (e.g., in the presence of a base such as sodium hydroxide,potassium hydroxide, lithium hydroxide and the like) or under an acidiccondition (e.g., in the presence of an acid such as hydrochloric acid,sulfuric acid and the like).

The amount of the base to be used is generally 1 to 10 mol, preferably 1to 5 mol, particularly preferably 1 to 2 mol, per 1 mol of compound[XV].

The amount of the acid to be used is not particularly limited.

The reaction condition is preferably a basic condition, and the reactionis particularly preferably carried out in the presence of sodiumhydroxide.

Examples of the solvent include alcohol solvents such as methanol,ethanol, n-propanol, isopropanol and the like; hydrocarbon solvents suchas toluene, hexane, xylene and the like; halogenated solvents such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloromethaneand the like; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran and the like; polar solvents suchas N,N-dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile and thelike; water or a mixed solvent thereof and the like, with preferencegiven to a mixed solvent of ethanol and water.

The reaction temperature is preferably 0° C. to 100° C., more preferably40° C. to 60° C.

The reaction time is preferably 0.5 hr to 12 hr, preferably 0.5 hr to 3hr.

In the workup, the pH of the reaction mixture is preferably 3-5.

EXAMPLES

A compound useful as a synthetic intermediate for an anti-HIV agenthaving an integrase inhibitory activity and a production method thereof,and a production method of an anti-HIV agent using the syntheticintermediate are specifically explained next. Those of ordinary skill inthe art will understand that the present invention is not limited tothese Examples.

Reference Example 1 Synthesis of 3-chloro-2-fluorobenzylzinc bromide

Under an argon atmosphere, a zinc powder (3.18 g) was suspended intetrahydrofuran (8 ml), 1,2-dibromoethane (0.061 g, 0.32 mmol) andtrimethylsilylchloride (0.071 g, 0.65 mmol) were successively added at60° C., and the mixture was stirred for 30 min. A solution of3-chloro-2-fluorobenzyl bromide (7.48 g, 32.5 mmol) in tetrahydrofuran(20 ml) was added dropwise to the solution prepared above at 60° C. Themixture was further stirred under heating for 1 hr to give a solution of3-chloro-2-fluorobenzylzinc bromide in tetrahydrofuran.

Reference Example 2 Synthesis of 3-chloro-2-fluorobenzylzinc chloride

Under an argon atmosphere, a zinc powder (1.44 g) was suspended intetrahydrofuran (3.6 ml), 1,2-dibromoethane (38 mg) and trimethylsilylchloride (43 mg) were successively added at 60° C., and the mixture wasstirred for 30 min. A solution of 3-chloro-2-fluorobenzylchloride (3.58g) in tetrahydrofuran (9 ml) was added dropwise at 60° C. to thesolution prepared above. The mixture was further stirred under heatingfor 1 hr to prepare a solution of 3-chloro-2-fluorobenzylzinc chloridein tetrahydrofuran.

Example 1 Step 1 Synthesis of 5-bromo-2,4-dimethoxybenzoic acid

2,4-Dimethoxybenzoic acid (30.0 g) was suspended in acetic acid (180mL). A bromine (27.6 g)/acetic acid (60 mL) solution was slowly addeddropwise to the suspension and, after completion of the dropwiseaddition, the mixture was stirred at 25° C. for 2 hrs, and thetermination of the reaction was confirmed by HPLC. An aqueous solutionof sodium sulfite (2.10 g) and water (360 mL) was added dropwise to thereaction mixture. After completion of the dropwise addition, the mixturewas stirred at 25° C. for 1 hr. Precipitated crystals were filtered,washed 4 times with water (150 mL), and vacuum dried to give5-bromo-2,4-dimethoxybenzoic acid as white crystals (41.2 g) (96%)

Step 2 Synthesis of methyl 5-bromo-2,4-dimethoxybenzoate

5-Bromo-2,4-dimethoxybenzoic acid (10.0 g) and con. sulfuric acid (2.4g) were added to methanol (80 mL). After reaction at 70° C. for 5 hr,completion of the reaction was confirmed by HPLC. The reaction mixturewas cooled and adjusted to pH 7 with 2 mol/L aqueous sodium hydroxidesolution, and ethyl acetate (50 mL) was added. The organic solvent wasevaporated from the mixture under reduced pressure. To the concentratedresidue was added ethyl acetate (50 mL), and the mixture wasconcentrated again under reduced pressure. To the concentrated residuewas added ethyl acetate (70 mL), and the mixture was stirred andpartitioned. The obtained organic layer was washed successively withwater (50 mL), 5% sodium hydrogencarbonate (50 mL) and water (50 mL).After washing, ethyl acetate was evaporated under reduced pressure togive methyl 5-bromo-2,4-dimethoxybenzoate (9.4 g) (90%).

Step 3 Synthesis of methyl5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoate

Under a nitrogen atmosphere, tris(dibenzylideneacetone)dipalladium(0)(318 mg) and triphenylphosphine (286 mg) were added to THF (40 mL), andthe mixture was stirred at room temperature for 1 hr. A solution ofmethyl 5-bromo-2,4-dimethoxybenzoate (5.0 g) obtained in theabove-mentioned Step 2/1-methyl-2-pyrrolidinone (40 mL) and a solution(23.4 g) of 29% 3-chloro-2-fluorobenzylzinc bromide in tetrahydrofuranwere successively added dropwise at room temperature. After dropwiseaddition, the mixture was stirred at 65° C. for 2 hr, and completion ofthe reaction was confirmed by HPLC. After cooling the reaction mixture,toluene (75 mL) and 12.5% aqueous ammonium chloride solution (50 mL)were added, and the mixture was thoroughly stirred and the aqueous layerwas discarded. The organic layer was washed successively with 25%aqueous ammonium chloride solution (25 mL), twice with 2% aqueousethylenediamine solution (25 mL) and three times with 10% brine (25 mL).After washing, the solvent was evaporated under reduced pressure to givemethyl 5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoate (6.81 g). Thiswas directly used in the next step.

Step 4 Synthesis of 5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoicacid

Methyl 5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoate was dissolvedin isopropanol (20 mL), and 1 mol/L aqueous sodium hydroxide solution(30 mL) was added. The mixture was stirred at 70° C. for 3 h, andcompletion of the reaction was confirmed by HPLC. After cooling thereaction mixture to room temperature, activated carbon (Sirasagi A) (1.0g) was added. After stirring, the mixture was filtered using powdercellulose (KC FLOCK). The reaction container and the filter were washedwith isopropanol (5 mL)/water (5 mL) solution, and combined with thefiltrate. Water (20 mL) and hexane (20 mL) were added to the obtainedfiltrate and, after stirring, the organic layer was removed. The aqueouslayer was washed again with hexane (20 mL). The aqueous layer wasice-cooled, methylisopropylketone (50 mL) was added while adding 2 mol/Lhydrochloric acid solution (10 mL) dropwise at 10° C. After theaddition, the mixture was stirred at room temperature and the aqueouslayer was discarded. The organic layer was washed twice with 10% brine(20 mL). After washing, the solvent was evaporated under reducedpressure to give 5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoic acid(4.8 g, yield 81%, from methyl 5-bromo-2,4-dimethoxybenzoate obtained inStep 2).

Step 5 Synthesis of 5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoicacid chloride

Under a nitrogen atmosphere,5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoic acid (4.7 g) wasdissolved in DMF/toluene solution (25 mL) (DMF concentration: 300 ppm).Thionyl chloride (2.1 g) was added dropwise to this solution at 75° C.After stirring at 75° C. for 1 hr, completion of the reaction wasconfirmed by HPLC. Toluene and excess thionyl chloride were evaporatedunder reduced pressure. Toluene (20 mL) was added to the concentratedresidue, and the mixture was concentrated again under reduced pressureto give 5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoic acid chloride(5.07 g). THF (15 mL) was added thereto to give a suspension of acidchloride (5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoic acidchloride) in THF, which was directly used in the next step.

Step 6 Synthesis of ethyl3-(5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxyphenyl)-3-oxopropionate

Under a nitrogen atmosphere, THF (5.23 g) was slowly added dropwise to asuspension of anhydrous magnesium chloride (3.45 g) in ethyl acetate (30mL). After completion of the dropwise addition, the mixture was stirredat 75° C. for 2 hr to dissolve anhydrous magnesium chloride. Thesolution was added dropwise to an ice-cold suspension of potassium ethylmalonate (4.94 g) and triethylamine (4.40 g) in ethyl acetate (20 mL).After dropwise addition, the suspension was warmed to 70° C. To thesuspension was slowly added dropwise a suspension of acid chlorideobtained in the above-mentioned Step 5 in THF at 70° C. After completionof the dropwise addition, the mixture was stirred at 70° C. for 0.5 hr,and the completion of the reaction was confirmed by HPLC. 2Nhydrochloric acid (30 mL) was added dropwise to the reaction mixtureunder ice-cooling, and the mixture was stirred at room temperature for0.5 hr. The organic layer was separated and washed successively withwater (25 mL), twice with 5% sodium hydrogencarbonate (25 mL), and water(25 mL). After the washing, the solvent was evaporated under reducedpressure, toluene (25 mL) was added to the concentrated residue and themixture was concentrated again under reduced pressure to give ethyl3-(5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxyphenyl)-3-oxopropionate(5.52 g).

Step 7 Synthesis of ethyl2-(5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoyl)-3-dimethylaminoacrylate

Under a nitrogen atmosphere, ethyl3-(5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxyphenyl)-3-oxopropionate(2.76 g) and N,N-dimethylformamide dimethyl acetal (1.36 g) weredissolved in toluene. This solution was stirred at 95° C. for 10 hr, andthe completion of the reaction was confirmed by HPLC. The reactionmixture was cooled to room temperature to give a solution of ethyl2-(5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoyl)-3-dimethylaminoacrylatein toluene. The reaction mixture was directly used in the next step.

Step 8 Synthesis of ethyl2-(5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoyl)-3-((S)-1-hydroxymethyl-2-methylpropylamino)acrylate

Under a nitrogen atmosphere, L-valinol (1.05 g) was added to thereaction mixture obtained in the above-mentioned Step 7. After stirringat room temperature for 3 hr, the completion of the reaction wasconfirmed by HPLC. 1 mol/L hydrochloric acid (15 mL) was added to thereaction mixture and, after stirring, the toluene layer was separated.The toluene layer was further washed successively with 1 mol/Lhydrochloric acid (15 mL), water (15 mL), 5% aqueous sodiumhydrogencarbonate solution (15 mL) and water (15 mL). After the washing,toluene was evaporated under reduced pressure, toluene (10 mL) was addedto the concentrated residue, and the mixture was concentrated againunder reduced pressure to give ethyl2-(5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoyl)-3-((S)-1-hydroxymethyl-2-methylpropylamino)acrylate(3.48 g). This was directly used in the next step.

Step 9 Synthesis of ethyl2-(5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoyl)-3-((S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropylamino)acrylate

Under a nitrogen atmosphere, ethyl2-(5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoyl)-3-((S)-1-hydroxymethyl-2-methylpropylamino)acrylateobtained in the above-mentioned Step 8 and imidazole (646 mg) were addedto THF (9.4 mL). A solution (2.39 g) of tert-butyldimethylsilyl chloridein 50% toluene was added dropwise to the solution at 50-70° C. Aftercompletion of the dropwise addition, the mixture was stirred at 50-70°C. for 3 hr, and the completion of the reaction was confirmed by HPLC.The reaction mixture was cooled, THF (19 mL) and 10% brine (24 mL) wereadded and, after stirring, the mixture was partitioned. The organiclayer was washed twice with 10% brine (24 mL). After washing, THF wasevaporated under reduced pressure, toluene (21 mL) was added to theconcentrated residue, and the mixture was concentrated again underreduced pressure to give a crude product. This was purified by columnchromatography (ethyl acetate/hexane (1v/2v)) to give ethyl2-(5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoyl)-3-((S)-1-(tert-butyldimethylsilanyloxymethyl)-2-methylpropylamino)acrylate(3.62 g, yield 79.7%, from5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoic acid obtained in Step4) as a yellow oil.

Step 10 Synthesis of1-[(S)-1-(tert-butyldimethylsilanyloxymethyl)-2-methylpropyl]-6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylicacid ethyl ester

Under a nitrogen atmosphere, ethyl2-(5-(3-chloro-2-fluorobenzyl)-2,4-dimethoxybenzoyl)-3-((S)-1-(tert-butyldimethylsilanyloxymethyl)-2-methylpropylamino)acrylate(2.0 g) was added to toluene (12 mL), and potassium carbonate (444 mg)and tetra-n-butylphosphonium bromide (1.09 g) were added. After stirringat 110° C. for 22 hr, tetra-n-butylphosphonium bromide (0.55 g), andthen potassium carbonate (44 mg) were added, and termination of thereaction was confirmed by HPLC. The reaction mixture was cooled, thenallowed to cool to room temperature, and THF (16 mL) and 10% brine (16mL) were added. The mixture was stirred and partitioned. The organiclayer was washed twice with 10% brine (16 mL). After the washing, THFwas evaporated under reduced pressure to give crude1-[(S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropyl]-6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylicacid ethyl ester as a solid. This was purified by column chromatography(ethyl acetate/hexane (2v/3v)) to give1-[(S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropyl]-6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylicacid ethyl ester (937 mg, yield 49.6%) as a yellow-white solid.

Step 11 Synthesis of6-(3-chloro-2-fluorobenzyl)-1-[(S)-1-hydroxymethyl-2-methylpropyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

1-[(S)-1-(tert-butyldimethyl-silanyloxymethyl)-2-methylpropyl]-6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylicacid ethyl ester (900 mg) was added to isopropyl alcohol (3.6 mL), and1N sodium hydroxide (3.6 mL) was added. After stirring at 70° C. for 3hr, the completion of the reaction was confirmed by HPLC. The reactionmixture was cooled, and allowed to cool to room temperature. n-Heptane(5 mL) was added and, after stirring, the mixture was partitioned. Theaqueous layer was washed with n-heptane (5 mL). 35% Hydrochloric acid(400 mg) was added to the aqueous layer, methylisopropylketone (10 mL)was added and, after stirring, the mixture was partitioned. The organiclayer was washed successively with 8.5% aqueous sodium hydrogencarbonatesolution (5 mL) (3 times), 0.5N hydrochloric acid (5 mL) containingsodium chloride (250 mg), and 10% brine (5 mL). After the washing,methylisopropylketone was evaporated under reduced pressure to give6-(3-chloro-2-fluorobenzyl)-1-[(S)-1-hydroxymethyl-2-methylpropyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (680 mg, yield 99.3%) as a yellow-white solid.

The compound obtained in Example 1, Step 11 was identified as compound(10).

The property data of the title compound in each step is as follows.

TABLE 1 Structural MS(ESI) formula ¹H-NMR M+

(DMSO-d₆, 300 MHz) δ (ppm): 3.91 (s, 3H), 3.95 (s, 3H), 6.78 (s, 1H),7.85 (s, 1H), 12.47 (s, 1H). 261 (Step 1)

(DMSO-d₆, 300 MHz) δ (ppm): 3.75 (s, 3H), 3.89 (s, 3H), 3.96 (s, 3H),6.80 (s, 1H), 7.86 (s, 1H). 275 (Step 2)

(DMSO-d₆, 300 MHz) δ (ppm): 3.71 (s, 3H), 3.86 (s, 3H), 3.87 (s, 3H),3.89 (s, 2H), 6.71 (s, 1H), 7.06-7.16 (m, 2H), 7.34-7.48 (m, 1H), 7.51(s, 1H). 339 (Step 3)

(DMSO-d₆, 300 MHz) δ (ppm): 3.86 (s, 3H), 3.87 (s, 3H), 3.89 (s, 2H),6.69 (s, 1H), 7.09-7.16 (m, 2H), 7.39-7.46 (m, 1H), 7.69 (s, 1H). 325(Step 4)

(DMSO-d₆, 400 MHz) δ (ppm): 1.21 (t, 3H, J = 14.4 Hz), 3.83 (s, 2H),3.85-3.90 (m, 8H), 4.07 (q, 2H, J = 14.4 Hz), 6.72 (s, 1H), 7.10-7.15(m, 2H), 7.42-7.45 (m, 1H), 7.52 (s, 1H). 395 (Step 6)

TABLE 2 Structural MS(ESI) formula ¹H-NMR M+

(DMSO-d₆, 400 MHz) δ (ppm): 0.00-0.01 (m, 6H), 0.79-1.00 (m, 10H), 0.85(s, 9H), 1.88-1.94 (m, 1H), 3.30-3.34 (m, 1H), 3.60-3.90 (m, 6H), 3.62(s, 3H), 3.84 (s, 3H), 6.58 (s, 1H), 6.87 (s, 1H), 7.10-7.15 (m, 2H),7.38-7.42 (m, 1H), 7.91 (d, 1H, J = 10.5 Hz). 622 (Step 9)

(DMSO-d₆, 300 MHz) δ (ppm): 0.00 (d, 6H, J = 3.4 Hz), 0.81 (s, 9H), 0.85(d, 3H, J = 6.7 Hz), 1.25 (d, 3H, J = 6.7 Hz), 1.33 (t, 3H, J = 7.1 Hz),2.40-2.48 (m, 1H), 3.93-3.97 (m, 1H), 4.06 (s, 3H), 4.09-4.15 (m, 3H),4.20-4.33 (m, 2H), 4.80-4.82 (m, 1H), 7.23-7.36 (m, 2H), 7.37 (s, 1H),7.53-7.57 (m, 1H), 7.97 (s, 1H), 8.66 (s, 1H). 590 (Step 10)

(DMSO-d₆, 300 MHz) δ (ppm): 0.73 (d, 3H, J = 6.7 Hz), 1.16 (d, 3H, J =6.4 Hz), 2.30-2.55 (m, 1H), 3.75- 3.85 (m, 1H), 3.95-4.10 (m, 1H), 4.04(s, 3H), 4.12 (s, 2H), 4.80-4.95 (m, 1H), 5.15-5.25 (m, 1H), 7.10-7.20(m, 1H), 7.20-7.25 (m, 1H), 7.40- 7.55 (m, 2H), 8.05 (s, 1H), 8.89 (s,1H), 15.4 (s, 1H). 448 (Step 11)

The analysis conditions of HPLC used in the above-mentioned Example 1are described in the following.

HPLC Analysis Conditions

analysis method 1 (Example 1, Step 1-Step 3)

analysis conditions

column: AM-302 5 μm (150 mm×4.6 mm i.d.) (YMC)

column temperature: 40° C.

mobile phase: mobile phase A: 0.01% aqueous TFA (trifluoroacetic acid)solution

mobile phase B: 0.01% TFA acetonitrile solution gradient program

TABLE 3 time (min) 0 5 15 20 35 45 55 56 65 mobile phase A 70 70 50 5030 20 20 70 stopped mobile phase B 30 30 50 50 70 80 80 30

flow rate: 1.0 mL/min

detection: UV 220 nm

analysis time: 55 min

analysis method 2 (Example 1, Step 4-Step 8)

analysis conditions

column: Inertsil ODS-80A 5 μm (150 mm×4.6 mm i.d.) (GL Sciences Inc)

column temperature: 40° C.

mobile phase: mobile phase A: 0.01% TFA aqueous solution

mobile phase B: 0.01% TFA acetonitrile solution gradient program

TABLE 4 time (min) 0 5 15 20 35 45 55 56 65 mobile phase A 70 70 50 5030 20 20 70 stopped mobile phase B 30 30 50 50 70 80 80 30

flow rate: 1.0 mL/min

detection: UV 220 nm

analysis time: 55 min

analysis method 3 (Example 1, Step 9-Step 11)

analysis conditions

column: Inertsil ODS-80A 5 μm (150 mm×4.6 mm i.d.) (GL Sciences Inc)

column temperature: 40° C.

mobile phase: mobile phase A: 0.01% aqueous TFA solution

mobile phase B: 0.01% TFA acetonitrile solution gradient program

TABLE 5 time (min) 0 5 15 20 35 45 65 66 75 mobile phase A 70 70 50 5030 20 20 70 stopped mobile phase B 30 30 50 50 70 80 80 30

flow rate: 1.0 mL/min

detection: UV 220 nm

analysis time: 65 min

Next, the compound of the present invention represented by the formula[I], which is useful as a synthetic intermediate for an anti-HIV agenthaving an integrase inhibitory activity and a production method thereof,and a production method of the anti-HIV agent using the syntheticintermediate are specifically explained. However, the present inventionis not limited by these Examples.

Example 2 Step I Synthesis of 3-chloro-2-fluorobenzylzinc bromide

Under an argon atmosphere, a zinc powder (3.18 g) was suspended intetrahydrofuran (8 ml), 1,2-dibromoethane (0.061 g, 0.32 mmol) andtrimethylsilyl chloride (0.071 g, 0.65 mmol) were successively added at60° C., and the mixture was stirred for 30 min. A solution of3-chloro-2-fluorobenzylbromide (7.48 g, 32.5 mmol) in tetrahydrofuran(20 ml) was added dropwise at 60° C. to the solution prepared above. Themixture was further stirred under heating for 1 hr to give a solution of3-chloro-2-fluorobenzylzinc bromide in tetrahydrofuran.

Step II Synthesis of 5-bromo-2-fluoro-4-methoxybenzoic acid methyl ester

While stirring under ice-cooling, con. sulfuric acid (14 ml) was addeddropwise to methanol (840 ml). Then, 2-fluoro-4-methoxybenzoic acid(70.0 g) was added and the mixture was stirred at 65° C. for 14 hr.After cooling the reaction mixture, bromine (152 g) was added dropwisethereto with stirring under ice-cooling. After dropwise addition, themixture was allowed to warm to room temperature and stirred for 20 hr.Water (840 ml) and sodium sulfite (71.9 g) were successively added.After the addition, the mixture was further stirred for 2 hr, and theprecipitated crystals were collected by filtration. The filtratedcrystals were washed twice with water (210 ml), and dissolved in toluene(560 ml). The toluene solution was washed successively with 5% aqueoussodium hydrogencarbonate solution (280 ml) and water (280 ml, twice).The organic layer was concentrated under reduced pressure and1-methyl-2-pyrrolidinone (700 ml) was added to the residue to allowdissolution to give 5-bromo-2-fluoro-4-methoxybenzoic acid methyl estersolution.

The compound was identified as the title compound by HPLC.

HPLC Conditions:

column: Inertsil ODS-80A (4.6×150 mm) (GL Sciences, Inc.)

mobile phase A: 0.01% aqueous TFA solution

mobile phase B: 0.01% TFA-MeCN solution

flow rate: 1 ml/min

column temperature: 40° C.

analysis time: 35 min

gradient

time (min): 0 10 20 35 36 45 mobile phase A: 70 50 20 20 70 Stop mobilephase B: 30 50 80 80 30 Stop

Step III Synthesis of5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoic acid methyl ester

Under a nitrogen atmosphere, tris(dibenzylideneacetone)dipalladium(0)(6.63 g) and triphenylphosphine (5.98 g) were successively added to1-methyl-2-pyrrolidinone (350 ml) with stirring at room temperature, andthe mixture was stirred for 1 hr. A solution of5-bromo-2-fluoro-4-methoxybenzoic acid methyl ester prepared in Example2, Step II, in 1-methyl-2-pyrrolidinone and a solution of3-chloro-2-fluorobenzylzinc bromide prepared in Example 2, Step I, intetrahydrofuran were successively added dropwise. After the dropwiseaddition, the mixture was stirred at 85° C. for 2 hr and cooled. To thereaction mixture were added toluene (560 ml) and 12.5% aqueous ammoniumchloride solution (980 ml) and the mixture was stirred. The organiclayer was washed successively with 25% aqueous ammonium chloridesolution (490 ml), 2% aqueous ethylenediamine solution (490 ml, twice)and 10% brine (490 ml, twice). After the washing, the solvent wasconcentrated under reduced pressure. Ethyl acetate (105 ml) and heptane(420 ml) were added to the residue to allow recrystallization to give5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoic acid methyl ester(106.8 g, yield 79.4%).

¹H-NMR (DMSO-d₆, 300 MHz) (δ) ppm: 3.79 (s, 3H), 3.86 (s, 3H), 3.96 (s,2H), 7.03 (d, 1H, J=12.8 Hz), 7.14 (m, 2H), 7.45 (m, 1H), 7.64 (d, 1H,J=8.1 Hz).

MS(ESI): M⁺ 327

Example 3 Synthesis of6-(3-chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid Step IV Synthesis of5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoic acid

5-(3-Chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoic acid methyl ester(100 g) obtained in Example 2, Step III was dissolved in1-methyl-2-pyrrolidinone (500 ml), and 2.5% V/W aqueous alkali solutionprepared from 8N-aqueous sodium hydroxide solution (54.7 ml) and water(192.6 ml) was added dropwise with stirring at room temperature. Afterthe dropwise addition, the mixture was stirred for 3.5 hr, and acidifiedby dropwise addition of 2N-hydrochloric acid (240 ml) with stirring atroom temperature. The precipitated crystals were stirred for 2 hr andcollected by filtration. The filtrate was washed with 50% methanolaqueous solution (100 ml) and dried at an outer temperature of 70° C. togive 5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoic acid (89.4 g,yield 93.4%).

¹H-NMR (DMSO-d₆, 300 MHz) (δ) ppm: 3.85 (s, 3H), 3.94 (s, 2H), 6.98 (d,1H, J=12.8 Hz), 7.15 (m, 2H), 7.44 (m, 1H), 7.60 (d, 1H, J=8.8 Hz), 12.8(s, 1H).

MS(ESI): M⁺ 313

Step V Synthesis of5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl chloride

5-(3-Chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoic acid (10 g)obtained in Step IV was suspended in toluene (50 ml), and thionylchloride (4.56 g) was added dropwise at 65-75° C. After the dropwiseaddition, the mixture was stirred for 1 hr and concentrated underreduced pressure. Toluene (30 ml) was added to the residue, and themixture was concentrated again under reduced pressure. The residue wasdissolved in toluene (30 ml) to give a solution of5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl chloride intoluene. This was identified as the title compound by HPLC.

HPLC conditions: Same as the HPLC conditions in the above-mentionedExample 2, Step II, except that 10% diethylamine-MeCN solution was usedas mobile phase B. Accordingly, a diethylamide form of the titlecompound was detected.

Step VI-2 Synthesis of3-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxyphenyl)-3-oxopropionicacid ethyl ester

Triethylamine (9.71 g) and magnesium chloride (7.61 g) were successivelyadded to a suspension of potassium ethyl malonate (10.8 g) intetrahydrofuran with stirring at room temperature. After stirring at60-70° C. for 1.5 hr, a solution of5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl chloride preparedin Step V in toluene was added dropwise, and the mixture was furtherstirred for 30 min. After cooling, toluene (50 ml) and 2N hydrochloricacid (60 ml) were added to the reaction mixture, and the mixture wasstirred for 1 hr. The organic layer was washed successively with water(50 ml), 5% sodium hydrogencarbonate (50 ml, twice), and water (50 ml)again, and the organic layer was concentrated under reduced pressure.Toluene (50 ml) was added to the residue, and the mixture wasconcentrated under reduced pressure. The residue was dissolved intoluene (50 ml) to give a solution of3-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxyphenyl)-3-oxopropionicacid ethyl ester in toluene. This was identified as the title compoundby HPLC.

HPLC conditions: Same as the HPLC conditions in the above-mentionedExample 2, Step II, except that 10% diethylamine-MeCN solution was usedas mobile phase B. Accordingly, a diethylamide form of the titlecompound was detected.

Step VIII Synthesis of2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-dimethylaminoacrylicacid ethyl ester

To a solution of3-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxyphenyl)-3-oxopropionicacid ethyl ester prepared in Step VI-2 in toluene was added dropwise at75-85° C. N,N-dimethylformamide dimethyl acetal (5.08 g) with stirring,and the mixture was stirred for 3 hr. After cooling, a solution of2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-dimethylaminoacrylicacid ethyl ester in toluene was obtained. This was identified as thetitle compound by HPLC. HPLC conditions: Same as the HPLC conditions inthe above-mentioned Example 2, Step II.

Step IX Synthesis of2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-((S)-1-hydroxymethyl-2-methylpropylamino)acrylicacid ethyl ester

To a solution of2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-dimethylaminoacrylicacid ethyl ester prepared in Step VIII in toluene was added(S)-2-amino-3-methylbutan-1-ol (3.96 g) with stirring at roomtemperature. After stirring for 30 min, 1N hydrochloric acid (60 ml) wasadded, and the mixture was further stirred for 1 hr. The organic layerwas separated and washed successively with water (60 ml), 5% sodiumhydrogencarbonate (60 ml) and water (60 ml). The organic layer wasconcentrated under reduced pressure, N,N-dimethylformamide (40 ml) wasadded to the residue, and the mixture was concentrated again underreduced pressure. The residue was dissolved in N,N-dimethylformamide (50ml) to give a solution of2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-((S)-1-hydroxymethyl-2-methylpropylamino)acrylicacid ethyl ester in N,N-dimethylformamide. This was identified as thetitle compound by HPLC.

HPLC conditions: Same as the HPLC conditions in the above-mentionedExample 2, Step II.

Step X Synthesis of6-(3-chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid ethyl ester

To a solution of2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-((S)-1-hydroxymethyl-2-methylpropylamino)acrylicacid ethyl ester prepared in Step IX in N,N-dimethylformamide was addedanhydrous potassium carbonate (4.86 g) with stirring at roomtemperature. After stirring at 95-105° C. for 6 hr,N,N-dimethylformamide (10 ml) and water (50 ml) were successively addeddropwise at 65-75° C. to allow crystallization. After stirring for 1 hr,the mixture was cooled to room temperature, and further stirred for 1hr. Water (20 ml) was further added and, after stirring for 1 hr, andthe mixture was filtrated, and the residue was successively washed with50% aqueous N,N-dimethylformamide solution (20 ml) and water (20 ml),and vacuum dried to give6-(3-chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid ethyl ester (13.5 g).

¹H-NMR (DMSO-d₆, 300 MHz) (δ) ppm: 0.74 (d, 2H, J=6.6 Hz), 1.14 (d, 2H,J=6.6 Hz), 1.26 (t, 3H, J=7.2 Hz), 2.29 (m, 1H), 3.78 (m, 1H), 3.94 (m,1H), 3.98 (s, 3H), 4.04 (s, 2H), 4.20 (q, 2H, J=7.0 Hz), 4.63 (m, 1H),5.11 (s, 1H), 7.21 (m, 3H), 7.47 (m, 1H), 7.88 (s, 1H), 8.62 (s, 1H).

MS(ESI): M⁺ 476

Step XI Synthesis of6-(3-chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid

6-(3-Chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid ethyl ester (5.0 g) was suspended in ethanol (30 ml), and 1.5% V/Waqueous alkali solution prepared from 8N-aqueous sodium hydroxidesolution (30 ml) and water (5.53 ml) was added dropwise with stirring atroom temperature. After stirring at 45-55° C. for 30 min, the mixturewas cooled, and 2N hydrochloric acid (7.88 ml) was added dropwise withstirring at room temperature. Then, a seed crystal (5 mg) of the titlecompound was added, and the mixture was further stirred for 1 hr. Afterfiltration, the residue was washed with 60% ethanol (10 ml) and vacuumdried to give6-(3-chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid (4.34 g, yield 92.9%) having a melting point of 166° C.

¹H-NMR (DMSO-d₆, 300 MHz) (δ) ppm: 0.73 (d, 2H, J=6.6 Hz), 1.16 (d, 2H,J=6.2 Hz), 2.48 (m, 1H), 3.78 (m, 1H), 3.98 (m, 1H), 4.03 (s, 3H), 4.11(s, 2H), 4.87 (m, 1H), 5.19 (s, 1H), 7.22 (m, 2H), 7.48 (m, 2H), 8.04(s, 1H), 8.88 (s, 1H).

MS(ESI): M⁺ 448

Synthesis of6-(3-chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid

6-(3-Chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid (8 g) obtained in Step XI was dissolved in acetic acid isobutylester (40 ml) at 110-120° C. and, after cooling to room temperature, aseed crystal (8 mg) of the title compound was added. After stirring atroom temperature for 5 hr, the precipitated crystals were collected byfiltration, washed with acetic acid isobutyl ester (8 ml) and vacuumdried to give6-(3-chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid (6.99 g, recovery rate 87.4%).

Example 4 Step V Synthesis of5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl chloride

5-(3-Chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoic acid (10 g) wassuspended in toluene (50 ml) with stirring at room temperature, thionylchloride (4.57 g) was added dropwise at 65-75° C., and the mixture wasstirred for 1.5 hr. After cooling, the solvent was concentrated underreduced pressure, toluene (50 ml) was added to the residue, and themixture was concentrated again under reduced pressure. The residue wasdissolved in toluene (20 ml) to give a solution of5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl chloride intoluene. This was identified as the title compound by HPLC. HPLCconditions: Same as the HPLC conditions in the above-mentioned Example2, Step II, except that 10% diethylamine-MeCN solution was used asmobile phase B. Accordingly, a diethylamide form of the title compoundwas detected.

Step VI-1 Synthesis of2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-oxobutyricacid ethyl ester

Barium oxide (6.54 g) was added to a mixed solution of water (0.69 g)and toluene (100 ml) with stirring under water-cooling, and the mixturewas stirred for 2 hr. Then, a solution of acetoacetic acid ethyl ester(4.99 g) in toluene (5 ml) was added under water-cooling, and themixture was stirred for 2 hr. A solution (20 ml) of5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl chloride obtainedin the same manner as in Example 3 or 4, Step V, in toluene was addedagain with stirring under ice-cooling. After stirring for 1 hr, 0.5Nhydrochloric acid (100 ml) was added dropwise, and the mixture wasfurther stirred for 2 hr. The organic layer was separated, washed 3times with 20% brine (50 ml), and concentrated under reduced pressure.Ethanol (100 ml) was added to the residue, and the mixture wasconcentrated again under reduced pressure. The residue was dissolved inethanol (100 ml) to give a solution of2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-oxobutyricacid ethyl ester in ethanol. This was identified as the title compoundby HPLC.

HPLC conditions: Same as the HPLC conditions in the above-mentionedExample 2, Step II, except that 10% diethylamine-MeCN solution was usedas mobile phase B. Accordingly, a diethylamide form of the titlecompound was detected.

Step VII Synthesis of3-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxyphenyl)-3-oxopropionicacid ethyl ester

To a solution of2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-oxobutyricacid ethyl ester prepared in Step VI-1 in ethanol were successivelyadded water (5 ml) and sodium acetate (7.87 g) with stirring at roomtemperature, and the mixture was stirred for 4 days. Water (20 ml) wasadded to the reaction suspension at 70° C. and, after confirmation ofdissolution, the mixture was cooled to room temperature. A seed crystal(10 mg) of the title compound was added and, after stirring for 1 hr,water (75 ml) was added again, and the mixture was stirred for 4 hr. Theprecipitated crystals were collected by filtration, washed with 50%ethanol (20 ml) and vacuum dried to give3-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxyphenyl)-3-oxopropionicacid ethyl ester (10.3 g, yield 84.5%). This was identified as the titlecompound by HPLC. HPLC conditions: Same as the HPLC conditions in theabove-mentioned Example 2, Step II.

Example 5 Step XII Synthesis of2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-dimethylaminoacrylicacid ethyl ester

Under a nitrogen atmosphere, 3-dimethylaminoacrylic acid ethyl ester(1.0 g) and N,N-diisopropylamine (1.07 g) were dissolved in toluene (6.0ml), and a solution of5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl chloride obtainedin the same manner as in Example 3 or 4, Step V, in toluene was addeddropwise at 75° C. After dropwise addition, the mixture was stirred for6 hr, and further heated under reflux for 5 hr. After cooling, asolution of2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-dimethylaminoacrylicacid ethyl ester in toluene was obtained. This was identified as thetitle compound by HPLC.

HPLC conditions: Same as the HPLC conditions in the above-mentionedExample 2, Step II.

Step XIII Synthesis of2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-((S)-1-hydroxymethyl-2-methylpropylamino)acrylicacid ethyl ester

To a solution of2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-dimethylaminoacrylicacid ethyl ester prepared in Step XII in toluene was added(S)-2-amino-3-methylbutan-1-ol (3.96 g) with stirring at roomtemperature. After stirring for 30 min, 1N hydrochloric acid (60 ml) wasadded, and the mixture was further stirred for 1 hr. The organic layerwas separated, and washed successively with water (60 ml), 5% sodiumhydrogencarbonate (60 ml) and water (60 ml). The organic layer wasconcentrated under reduced pressure. N,N-dimethylformamide (40 ml) wasadded to the residue, and the mixture was concentrated again underreduced pressure. The residue was dissolved in N,N-dimethylformamide (60ml) to give a solution of2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-((S)-1-hydroxymethyl-2-methylpropylamino)acrylicacid ethyl ester in N,N-dimethylformamide. This was identified as thetitle compound by HPLC.

HPLC conditions: Same as the HPLC conditions in the above-mentionedExample 2, Step II.

Step XIV Synthesis of6-(3-chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid ethyl ester

To a solution of2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-((S)-1-hydroxymethyl-2-methylpropylamino)acrylicacid ethyl ester prepared in Step IX or Step III inN,N-dimethylformamide was added anhydrous potassium carbonate (4.86 g)with stirring at room temperature. After stirring at 95-105° C. for 6hr, N,N-dimethylformamide (10 ml) and water (50 ml) were successivelyadded dropwise at 65-75° C. to allow crystallization. After stirring for1 hr, the mixture was cooled to room temperature and further stirred for1 hr. Water (20 ml) was further added and, after stirring for 1 hr, themixture was filtered, and the residue was washed successively with 50%aqueous N,N-dimethylformamide solution (20 ml) and water (20 ml), andvacuum dried to give6-(3-chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid ethyl ester (13.5 g)).

Step XV Synthesis of6-(3-chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid

6-(3-Chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid ethyl ester (5.0 g) was dissolved in ethanol (30 ml), and 1.5% V/Waqueous alkali solution prepared from 8N-aqueous sodium hydroxidesolution (30 ml) and water (5.53 ml) was added dropwise with stirring atroom temperature. After stirring at 45-50° C. for 30 min, the mixturewas cooled, and 2N hydrochloric acid (7.88 ml) was added dropwise withstirring at room temperature. Then, a seed crystal was added, and themixture was further stirred for 1 hr. The mixture was filtered and theresidue was washed with 60% ethanol (10 ml) and vacuum dried to give6-(3-chloro-2-fluorobenzyl)-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline)-3-carboxylicacid (4.23 g, yield 89.8%).

This application is based on a patent application Nos. 2006-60277 and2006-60298 filed in Japan, the contents of which are incorporated infull herein by this reference.

INDUSTRIAL APPLICABILITY

The compound (2′) of the present invention is particularly useful as asynthetic intermediate for a compound having an extremely high HIVintegrase inhibitory activity (see, for example, WO2004/046115).

In addition, the present invention can provide a method of producing acompound having an HIV integrase inhibitory activity in a good yield.

Moreover, the production method of the present invention is useful as amethod for industrial mass synthetic because the method does not use ahighly dangerous and highly toxic reagent requiring careful handling andcan be performed under mild conditions.

1-33. (canceled)
 34. A compound of the following formula (7):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group and R²⁰⁰ is a hydroxyl-protectinggroup.
 35. A compound of the following formula (6):

wherein R is a fluorine atom or a methoxy group, and R¹⁰⁰ is a C₁-C₄alkyl group.
 36. A compound of the following formula (5):

wherein R is a fluorine atom or a methoxy group, and R¹⁰⁰ is a C₁-C₄alkyl group.
 37. A compound of the following formula (4):

wherein R is a fluorine atom or a methoxy group, and R¹⁰⁰ is a C₁-C₄alkyl group, or a salt thereof.
 38. A compound of the following formula(4-1-B):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, or a salt thereof.
 39. A compoundof the following formula (4-2-B):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, or a salt thereof.
 40. A compoundof the following formula (4-1-A):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, or a salt thereof.
 41. A compoundof the following formula (4-2-A):

wherein R¹⁰⁰ is a C₁-C₄ alkyl group, or a salt thereof.
 42. A compoundof the following formula (3):

wherein R is a fluorine atom or a methoxy group.
 43. A compound of thefollowing formula (2′):

wherein R is a fluorine atom or a methoxy group, and R⁴⁰⁰ is a hydrogenatom or a C₁-C₄ alkyl group, or a salt thereof.
 44. A compound of thefollowing formula: